Intrauterine fetal growth restriction - The biochemical rationale of treatment modalities including extraperitoneal transamniotic fetal supplements

ABSTRACT

Intrauterine fetal growth restriction (IUGR) is an affliction of a disparaging spectrum, placental insufficiency being the major inciting pathology. The resultant fetal hypoglycemia is alleviated by intravenous hypertonic D-glucose 25-50% maternal supplements, by improving the Vmax of placental transfer for D-glucose, in accordance with Michaelis-Menten model of substrate transfer. Fetal normoglycemia so restored in turn surprisingly improves fetal hypoxia, hypercapnia, hyperlacticemia, acidosis, hypertriglyceridemia, oliguria/hydromnios, and the fetal nutrient/mineral/vitamin acquisition. The list being phenomenal can only convince an inquiring reader by a biochemical sojourn into the aquatic world of the fetus, herein described. Maternal carbohydrate-predominant IUGR diet with maximal amounts of vitamin/mineral supplements are highly beneficial. Transamniotic isotonic D-glucose supplements via minimally invasive suprapubic extraperitonial pelvic approach and amniotomy (Sumathi Paturu&#39;s technique), with a subcutaneously implanted pregnancy port (SIPP) catheter is the additional therapy advocated.

INTRODUCTION

The embodiment of this invention is directed to an exemplary and aninnovative treatment involving ‘Intra Uterine Growth Restriction’ (IUGR)of a human fetus, a long known and incurable but treatablematernal-fetoplacental pathology, resulting in significant mortality andmorbidity of the fetus/neonate. The basic and clinical science researchfor alleviation of this elusive disease by investigators world-wide, isso far disappointing. The author inventor endeavors to disclose in thisspecification a simple yet clinically proved successful treatment, andit's biochemical basis. For a disease so disparagingly prevailed fordecades, the said treatment disguised as simple, nevertheless demandedramifications of it's rationale that are by no means simple, and effortshad been made to elaborate it with an infallible scientific reasoning ofa compelling depth and breadth, as never done before of the subjectmatter. One can envision the alleviation in toto of a formidablepathology, as if the pieces of an intricate puzzle were put together. Itfurther needed to counter the skepticism of an inquiring reader that isonly viewed as truly justified. Hence the following elaboration hasbecome arduous and rather voluminous, the author inventor also being noless skeptical and inquiring.

The definition for IUGR fetus/small for gestational age (SGA) infant isas follows—

‘Fetuses afflicted with intrauterine growth restriction (IUGR) ofwhatever etiology, or small for gestational age (SGA) neonates/infantsof whatever etiology are those whose estimated/attained birth weightsare below the tenth percentile, for the corresponding gestational age.’

The most common cause of intrauterine growth restriction (IUGR) of ahuman fetus is vascular in nature, resulting in placental vascularinsufficiency, thus decreasing the transfer of D-glucose (thedextro-isomeric form of glucose), the prime fetal nutrient, across theplacenta. Accordingly, as an interventional measure to alleviate thefetal IUGR of placental insufficiency, the specification enumerates atherapeutic measure of transamniotic isotonic D-glucose supplements inthis continuation-in-part (CIP) application, however such treatment isin addition to the concommitant maternal intravenous (IV) hypertonicD-glucose supplements invariably required for the reasons that will beelaborately explained. Such interventions working in conjunction cancounter the fetal hypoglycemia (defined as a sub-optimal blood glucoseconcentration), and also as a result the other associated metabolicderangements accountable for placental insufficiency.

BRIEF DESCRIPTION OF THE INVENTION

The specification is directed to a novel invention encompassing many ofunanticipated modalities in the specified treatment for intrauterinegrowth restriction (IUGR) of a human fetus, mainly due to placentalinsufficiency.

Chronic placental insufficiency of vascular nature decreases theplacental transfer of D-glucose. The other metabolic derangements alsoresulting from placental insufficiency like fetal hypoxia (ademand/supply mismatch of oxygen at the tissue level having immediate ordelayed adverse consequences) to mention the most menacing of the group,can be countered to a significant extent by the fetus, once hypoglycemiahas been corrected, whereas there are of no fetal devices to correctit's hypoglycemia in the first place. A disclosure of providingtransamniotic fetal supplements of 5% DEXTROSE (the dextroisomeric formof glucose or D-glucose) is herein described, as an additionaltherapeutic measure of effectively by-passing the placental impedance,after the fetus has been found to be not optimally responsive to anexhaustively implemented maternal intravenous (IV) hypertonic D-glucosesupplements, thus accomplishing a means of improving fetal hypoglycemia,and consequently of the associated problems of placental insufficiency.

The Maternal Intravenous or Transamniotic D-Glucose Treatments Improvethe Following Adverse Fetoplacental Consequences, Deficiencies, or ofOther Effects, Resulting from Placental Vascular Insufficiency/FetalHypoglycemia—1. Improvement of fetoplacental hypoxia.2. Improvement of fetal hypercapnia (above normal blood CO₂ that canhave adverse effects).3. Improvement of fetal oliguria (suboptimal urine production) andoligohydromnios (suboptimal amniotic fluid volume, corresponding to thegestational age)—with or without low fetal urea production.4. Improvement of fetal acidosis (excess hydrogen ion concentration inthe blood, leading to lowering of blood pH), including ketoacidosis.5. Improvement of fetal Hyperlacticemia (excess of blood lactate levels)leading to lactic acidosis or else pyruvic acidosis, that need a specialand separate mention apart from acidosis specified under subsection-4.6. Improvement of fetal hypertriglyceridemia (the triglyceridescirculating in the blood in a concentration above the normal standardvalue, or range).7. Improved acquisition by the fetus, of major nutrients likeessential/non-essential amino acids, fatty acids, and also of minerals,vitamins, and trace elements.8. Improvement of the following, by the effect of primarily D-glucosederived-ATP mediated active transport: (a) placental L-arginine uptakefor synthesis of nitric oxide responsible for fetoplacentalvasodilatation and for placental vasculogenesis through angiopoietinsignaling molecules, (b) placental D-lysine uptake responsible forfetal/placental neovasculogenesis—both in turn improving feto-placentalhypoperfusion, hypoxia, and an over all feto-maternal exchange.9. Improved growth and maturation of vital organs like fetal brain, forwhich optimal circulating D-glucose is essential, as the parentmolecule/building block for the brain's phospholipids and glycolipids.10. Improved production of ATP, the ultimate key, as the ubiquitous needfor all life forms, and for all life sustaining subcellular activities,being generated by citric acid cycle, the final pathway of thepredominantly prevailing glucose metabolism within the normal fetus,though it is also the ultimate meeting point for all major metabolicpathways including those of proteins and lipids.

Transamniotic Isotonic Dextrose Fetal Supplements

Transamniotic fetal supplement of isotonic 5% dextrose is advisable totreat severely growth restricted fetuses after the fetoplacental primingby the prior maternal IV hypertonic D-glucose supplements, and aftersuch associated therapeutic modalities are exhausted. The phenomenon ofin-utero fetal swallowing of amniotic fluid (AF) is taken advantage of,in this additional modality of treatment.

The majority of the physiochemical improvements or consequences ofimproved fetal hypoglycemia accomplished through maternal IV D-glucosesupplements are expected to be operative in the fetus with thistherapeutic modality also, achieved by means of by-passing the afflictedplacenta and directly involving the fetus, through the medium ofamniotic fluid that surrounds it.

Through a Subcutaneously implanted pregnancy port (SIPP) catheter, adevice specifically modified for obstetric purposes, the amniotic cavityis approached by a safe and minimally invasive surgical procedureaccomplished through an extraperitoneal route for which a novelprocedure is devised by the author inventor of this specification. Theport is used encompassing a ‘sterile patch technique’ also devised bythe author inventor to make the use completely sepsis-free so that thedevice is incorporated in the treatment with total confidence.

BRIEF DESCRIPTION OF THE DRAWINGS

1. FIG. 1A, FIG. 1 B, AND FIG. 1C: are the schematic illustrations ofthe specific effects of increased substrate (D-glucose) concentrationand as a result, it's heightened placental transport, as an expressionof MICHAELIS-MENTEN EQUATION that models the general effects ofsubstrate concentration on the velocity of the reaction rate, saideffects being applicable to all the three clinical situationsillustrated in FIG. 1A, FIG. 1B & FIG. 1C, and are described below—

FIG. 1 A: A schematic illustration of the placental D-glucose transportin normal pregnancy—said transport involving the substrate (in thiscase, the D-glucose) in normal physiological concentrations of thematernal blood/placental sinusoids.

FIG. 1 B: A schematic illustration of the placental D-glucose transportin an untreated IUGR pregnancy of placental insufficiency—depictingreduced number of tertiary stem villi involved in the transport of thesubstrate (in this case, the D-glucose) in normal physiologicalconcentrations of the maternal blood/placental sinusoids.

FIG. 1 C: A schematic illustration of the placental D-glucose transportin IUGR pregnancy of placental insufficiency, treated with maternalhypertonic IV D-glucose supplements—said treatment resulting inexceeding maternal/sinusoidal concentration of substrate (theD-glucose), and a consequent heightened maximal reaction rate (the Vmax) leading to improved placental D-glucose transport—as an effect andexpression of MICHAELIS-MENTEN EQUATION that models the effect ofsubstrate concentration on the rate of reaction velocity.

2. FIG. 2: A schematic illustration of glycolysis, and it's links tovarious related biochemical pathways. It depicts

-   -   The aerobic pathway of the D-glucose metabolism (shown as the        main pathway leading into the citric acid cycle).    -   The anaerobic pathway of the D-glucose metabolism (shown as a        pathway depicted in the left half of the illustration).    -   The conjunctional role of glycolysis-citric acid cycle in fetal        lipogenesis (shown as the pathways depicted in the right half of        the illustration).

3. FIG. 3: A schematic illustration of the biochemical steps of theMalate Shuttle—depicted as an ongoing operation between glycolysis andthe citric-acid cycle, as a means of transferring the cytosolic reducingequivalents (the 2H⁺) into the mitochondria.

4. FIG. 4: A schematic biochemical illustration of the citric acidcycle—that is the ultimate aerobic pathway of the D-glucose catabolismshowing the generation of the reducing equivalents (4 NADH+H⁺ and 1FADH₂), the generation of one substrate level ATP, and the generation of3 carbon dioxide (CO₂) molecules, via combustion of a single molecule ofpyruvate, the figure also including the formation of acetyl-CoA (frompyruvate) that enters into citric acid cycle.

5. FIG. 5: A schematic illustration of the biochemical pathway of themitochondrial oxidative phosphorylation—also depicting the ultimatemerging of the carbohydrate, protein, and of the lipid metabolicpathways into the citric acid cycle, and further depicting the transferof reducing equivalents, the 2H⁺ (the protons) to the mitochondrialrespiratory chain, so generating ATP, via the coupling of oxidation andphosphorylation.

6. FIG. 6: A schematic illustration of the biochemical pathways of‘Lipogenesis via Glycolysis and Abbreviated Citric acid Cycle’ (LGACC)in the fetal tissues.

7. FIG. 7: A perspective right sagittal view (a median section)illustrating the normal anatomy of the human pelvis and the lowerabdomen during pregnancy.

8. FIG. 8: A perspective right sagittal view illustrating the normalchanges in the peritoneal anatomy of the pelvis/lower abdomen with adistended bladder, as also seen during human pregnancy.

9. FIG. 9: A perspective illustration of a suprapubic extraperitonealamniotomy through the anterior lower uterine segment—involving a methodof insertion of a Subcutaneously Implanted Pregnancy Port (SIPP)catheter, depicted in an erect right lateral position, of a surgerygenerally performed in maternal supine position.

10. FIG. 10: A perspective view of a Subcutaneously Implanted PregnancyPort (SIPP), and the distal end of it's articulating port catheter—as aninstrument devised for obstetric purposes during human pregnancy.

11. FIG. 11: A perspective view of the proximal end of a SubcutaneouslyImplanted Pregnancy Port (SIPP) Catheter, with an attachable wingedcuff—the said cuff devised to anchor the proximal SIPP catheter to theexterior of the lower uterine segment, following an amniotomyintrauterine insertion of the proximal end of the SIPP catheter.

DETAILED DESCRIPTION OF THE INVENTION

This embodiment of invention is directed to an exemplary and noveltreatment for the Intra Uterine Growth Restriction (IUGR) of a humanfetus, a maternal-fetoplacental pathology, resulting in significantmortality and morbidity of the fetus/neonate. The specificationencompassing a biochemical, clinical, and surgical discussion ofcompelling depth and of breadth, envisions total alleviation of amulti-faceted disease, for long elusive and misunderstood. Placenta,exalted to the central stage among the fetal membranes, can beconsidered as an indispensable structural and functional appendage ofmany organ systems of the fetal body that the neonate disposes off,after it's nine months of intrauterine stay. Placenta being so crucial,it's dysfunction or insufficiency often makes an indelible mark on thefetus, affecting diverse aspects of prime functions ofgaseous/nutrient/substance exchange including selective transport ofpassing or restricting of certain maternal plasma components, andsynthesizing in alliance with the fetus, optimal quantities of pregnancyhormones essential throughout gestation, that the term feto-placentalunit is aptly phrased.

Chronic placental insufficiency of vascular nature decreases theplacental transfer of D-glucose that was noted earlier as the mostimportant of the fetal nutrients, resulting in on-going fetalhypoglycemia. The other metabolic derangements also resulting fromplacental insufficiency, like fetal hypoxia, to mention the mostmenacing of the group, can be countered by the fetus, once thehypoglycemia has been corrected, whereas there are of no fetal devicesto correct it's hypoglycemia in the first place. A disclosure of a meansof transamniotic fetal supplementation of 5% DEXTROSE infused through anovel device named Subcutaneously Implanted Pregnancy Port (SIPP)catheter, and a novel suprapubic extraperitoneal transamniotic insertionof the said SIP port-catheter are herein described, an additionaltherapeutic measure to resort to, for effectively by-passing theplacental impedance (after the fetus had been found to be unresponsiveto the exhaustive therapeutic modalities associated with the maternalintravenous hypertonic glucose supplements), thereby accomplishing ameans of improving the fetal hypoglycemia.

An accelerated ‘facilitated diffusion’ can be achieved at the placentalinterface by therapeutically creating a transient and intermittentmaternal hyperglycemia (defined as a rise in blood glucose concentrationabove specified normal range) by 25-50% hypertonic D-glucose bolusinfusion to the mother, given over multiple times of a day, after it isconfirmed that fetal IUGR is of placental vascular origin, and suchmaternal treatment continued until the delivery of the fetus/neonate

In a clinical setting as complex as fetal IUGR, the isolatedtransamniotic treatment of fetal nutrients is not deemed effective. Theplacenta consumes as much as 50-60% of glucose and even in diseasedstates it is responsible to metabolize, transform, transport, andsynthesize for and in alliance with the fetus many substances that arenecessary for optimal pregnancy outcome, like glucose/lactate transport,estriol synthesis—to mention a few, and in addition, accomplishesenergy/ATP consuming active transport-concentration of essentialnutrients and biologic substances via primarily glucose-generated ATP.Therefore, it can be evident that the transamniotic glucose supplementalone is a moot pursuit, if not done in conjunction with maternalintravenous hypertonic glucose supplements also, as such concomitanttherapy nourishes the feto-placental unit, which through out pregnancyis both a structural and a functional unit. The question of theeffectiveness of the transamniotic D-glucose supplements can only beanswered if such needed and invariable functional accompaniments aresomehow helped to be achieved by the afflicted placenta. Otherwise,intrauterine demise of the fetus happens despite an apparently adequatetransamniotic D-glucose treatments. Transamniotic D-glucose supplementis the last step in the algorithmic tree (discussed in the second halfof this specification) of the treatment for intrauterine fetal growthrestriction, as it is also an invasive procedure. Accordingly, thephysician should know in no uncertain terms why, how, and in whatcircumstances the transamniotic D-glucose treatment needs to beclinically pursued.

The great therapeutic effects firmly linked to the objectivephysiochemical principles of the D-glucose supplements and the rationaleare described first under the section of THE MATERNAL INTRAVENOUSHYPERTONIC D-GLUCOSE TREATMENTS, the discussion of which is ratherelaborate, and hence is not further repeated under the section THETRANSAMNIOTIC FETAL D-GLUCOSE SUPPLEMENTS via the SIPP catheter,encountered in the last part of this specification.

A Case Study

At the outset, it is relevant to describe a clinical case study ofsuccessfully treating a severe case of fetal IUGR, during the years1983-84, by the author inventor as a practicing ob/gyn in India, as itis the basis for this writing of significant depth that aided the authorinventor decades later to fully comprehend what was once successfullytreated, but was only incompletely understood at that time.

This single case study was with reference to a primi-gravida in herearly twenties who was found to have severely growth restricted fetus inthe middle of second trimester. She was well nourished and was from goodsocioeconomic background, and there were no obvious etiological factors,that could be accounted for the identified fetal IUGR. After monitoringthe growth of the fetus by assessing fundal height (a clinical norm offetal measure in the past) for 3-4 more weeks, it was confirmed that theuterine size was not progressing, and that the patient had severelygrowth restricted fetus. As the pregnancy was remote from term, and asthe bed rest in left lateral position had not helped, 20% IV bolus ofhypertonic D-glucose 50 cc twice daily was started, and in 2-3 weeks, animmediate catch up of fetal growth was undoubtedly observed. The patienthad more frequent pre-natal follow ups, and the treatment was diligentlycontinued, as also the patient was admirably cooperative. Nearing term,she was delivered by elective cesarean section. The baby had an apgarscore of 10, and to the great delight of everybody involved, the weightwas also appropriate for the gestational age (AGA). No adverse effectsdue to induced maternal hyperglycemia were expected, nor were anyobserved through-out the gestation, and the patient tolerated thetreatment far beyond expectations.

The observed fetal growth restriction was undoubtedly severe, but withmere hypertonic intravenous D-glucose treatment and no other (except forstandard doses of prenatal vitamins and minerals), the mother deliveredan AGA baby, who obviously had caught up with standard growth curve, asthough mere glucose supplements and nothing else was needed. It wasevident that by mere fetal normoglycemia therapeutically restored, thefetus alleviated multitude of associated metabolic problems all byitself.

A Clinical Model as the Basis for the Treatment—

Fetal macrosomia, a known consequence of uncontrolled maternal diabetesmellitus (DM) served as a clinical model about which the therapeuticmodality of this invention was/is based. Maternal hyperglycemia withoutsuper-concentration of any other element or of nutrient in the maternalblood, can accomplish accelerated fetal growth in diabetes mellitus. Itexemplifies not only of an accelerated placental glucose transfersecondary to maternal hyperglycemia, but also of an accelerated fetalgrowth response to such accelerated transfer. Extensive research by pastinvestigators in this subject matter proved beyond reasonable doubt thatfetal growth is indeed mediated by fetal hyperglycemia, and secondaryfetal hyperinsulinism (hyperinsulinemia), via the islet-cell hypertrophyof the fetal pancreas. Accordingly, this superb clinical model provedthe normal placental ability of accelerated glucose transfer, and of theresultant fetal growth response by macrosomia, both together serving asthe needed translational clinical outcome to the biochemical phenomenonof maternal hyperglycemia—a naturally observed consequence that mightnot have been otherwise available or proven, except by targetedresearch. However, the difference between the diabetic pregnancy and thetreatment setting of IUGR in the above discussed case study—that is, theglaring prevalence/perception of fetal hypoxia, hypercarbia(hypercapnia) (as described by past researchers), and of acidosis due toplacental insufficiency of IUGR is by no means over looked in thisdiscussion

Though a single case study, it was extraordinarily impressive because ofthe severity of growth restriction, and the lack of confoundingvariables (one can be 100% sure that Indian women are never habituatedto alcohol, smoking, or drugs) that clinched the diagnosis of a primaryplacental insufficiency of vascular origin. The present writingpainstakingly endeavors to explore a physiochemical support for thespecified invention—how the fetus, by mere restoring of it'snormoglycemic state, or improving of a hypoglycemic state, could havepossibly accomplished such an impossible feat, undoubtedly witnessed,though until this time, not completely understood.

The Maternal Intravenous Hypertonic D-Glucose Treatments

In the diverse maternal/fetal states that cause fetal IUGR, the diseaseprimarily afflicting placental vasculature causes more of declinedfunctional unit area than declined unit volume of the placenta,primarily due to failed placental elaboration (into tertiary terminalvilli within the normally mature placenta, over all attaining thestructural intricacy of a branching tree, that it is aptly called as the‘placental tree’). Such placental decline in the functional unit areawith decrement nutritional exchange in it's interface has resulted infetal hypoglycemia, and consequently in fetal growth restriction.

Based on the foregoing clinical model of diabetic pregnancy, and basedon the fact that the D-Glucose is the prime fetal nutrient, theinvention contemplates a biochemical and clinical relief, achieved bytherapeutic transient hyperglycemia effectuated in the mother (aninduced diabetic state) by intravenous 25-50% hypertonic D-glucose bolusinfusion, 50-100 cc twice or thrice daily. By such superconcentration ofglucose achieved via an IV infusion to the mother, the deprived fetalcirculation receives proportionally more D-glucose, presented throughthe placenta in higher concentration per unit surface area/unit volumeof it's yet unchangeable anatomically afflicted milieu. The function ofplacental glucose carrier proteins operating that far in a sub-optimallevel, becomes maximal during the transient maternal hyperglycemicphase—a biochemical phenomenon explained in significant detail in theimmediate subsequent sections.

Chronic vascular disease of the mother, especially pre-eclampsia wasconventionally linked as the predominant cause of fetal growthrestriction, mediated through placental vascular insufficiency. A widespectrum of generalized placental vascular insufficiency (of what everetiology) is the major pathology of concern to be alleviated through thetherapeutic modality of the present invention. Normally, as pregnancyadvances the uteroplacental blood flow gradually increases mainly due tospiral arterial remodeling. Very early on, due to trophoblasticinvasion, the endothelium and the smooth muscle layers of the myometrialspiral vessels are replaced with loss of spiral artery vascularresistance. The lacunae further created in the syncytiotrophoblast bycytotrophoblastic invasion, and their filling with blood results indilated pools of maternal blood sinusoids that are responsible for theshunt effect of the placenta. In an IUGR pregnancy, the trophoblasticinvasion is limited to the decidual endometrium with failure ofmyometrial spiral arteries becoming low resistance vessels. Suchplacental failure in surface area elaboration and failure in sinusoidalvolume/pressure effect dynamics can find relief by exceeding substratesupplements, as will be soon explained by the biochemically derivedprinciples of transcellular substrate transport.

Although diffusion across by concentration gradient (via carriermediated facilitated diffusion) has been described as an importantmethod of placental transfer, the trophoblast/chorionic villus unit doesexhibit enormous selectivity of transfer, maintaining differentconcentrations of a variety of metabolites on the two sides of thevillus (via ATP/energy expending, carrier mediated ‘active transport’, aplacental concentrating process against a concentration gradient). Itwas deduced by the observation that the concentrations of a number ofsubstances that have not been synthesized by the fetus are found severaltimes higher in the fetal blood than in the maternal blood. In contrast,the transfer across the placenta of D-glucose, the prime fetal substratecentral to this discussion, is accomplished by carrier mediated,stereospecific, and non-concentrating no-energy expending process thatcan be saturated, said process termed as ‘facilitated diffusion’.

The Biochemical Basis for Hypertonic D-Glucose Treatment

The Michaelis-Menten equation is an expression of the relation ofsubstrate concentration and the resultant rate of an enzyme/hormone/acell membrane-cytosol located substrate-carrier mediated chemicalreaction, either by active transport or by facilitated diffusion.

(In what follows, the D-glucose needs to be considered as the‘substrate’, and the GLUT-1 & GLUT-3 as it's substrate-carriers, locatedin the placental membrane. The enzyme/hormone involvement is alsoemphasized, the hormone relevant in this context being insulin)

In a typical chemical reaction involving an enzyme/hormone, or in amembrane transport mediated by a substrate-carrier (involving eitheractive transport or facilitated diffusion), if the concentration of thesubstance/substrate (S) is increased while all other factors are keptconstant, the measured initial velocity v₁ (the velocity attained whenvery little substance/substrate (S) has reacted with it'senzyme/hormone/carrier) increases until it reaches a maximum attainablevelocity (V_(max)) and can increase no further, even with furtherincrease of the substance/substrate (S), when the enzyme/hormone orcarrier is said to be saturated.

If (S) is the substance/substrate concentration, the ‘Michaelisconstant’ (K_(m)) is the substance/substrate concentration at which theinitial velocity v₁ is half of the maximal attainable velocity(V_(max)/2) at a particular concentration of the enzyme or carrierinvolved/available in a reaction. When (S) is approximately equal toK_(m) value, v₁ is very responsive to changes in (S), and theenzyme/carrier is working at half maximal efficiency. When thesubstance/substrate concentration (S) far exceeds the K_(m) value, theinitial velocity v₁ is maximal (V_(max)). Furthermore, in this situationthe reaction's maximal velocity V_(max) is almost instantaneous, as allthe available enzyme/carriers are able to bind to the exceeding amountsof substance/substrate (S) all at once, and no further binding possible.

Machaelis-Menten expression shows in mathematical terms the relationshipbetween the attained initial reaction velocity v₁, and the reactingsubstrate/substance concentration (S), as depicted below—

$V_{1} = \frac{{Vmax}(S)}{{Km} + (S)}$

Under physiological D-glucose concentrations of the maternal blood, theplacental carrier transporters for glucose were found to be far inexcess, with a reserve able to be accommodating further addition of anexceeding amount of D-glucose presented at the placental interface. Thisimplies that the carriers are always functioning in suboptimal mannerunder physiological concentrations. Insulin heightens the recruitment ofsuch carrier molecules from the intracellular pool. At times ofplacental compromise, the unit surface area of placental terminal villiare still transporting glucose in a manner similar to unaffectedplacental villi. However, the underlying problem in IUGR is the markedlyreduced total surface area/volume of the terminal villi secondary tofailed placental elaboration, and as a result markedly diminished numberof terminal villi that diminish the over-all glucose transport throughthe available total surface area of the placenta, per unit time. Itimplies, therapeutic maternal hyperglycemia with increasedsubstrate/glucose (S) concentration can recruit more of carriers perunit surface area of the villi, that is, the carrier molecules availablein surplus, now function at maximum rate to transport far exceedingamounts of glucose across the yet unchanged placental interface in unittime, as increased substance/substrate (S) concentration not onlyincreases v₁ to V_(max) (a maximal attainable speed) of each transportcarrier, but also increases the number of such maximally functioningcarriers in the unit placental surface area, now recruited in highernumber (as a result of increased insulin levels proportional toincreased D-glucose), due to the demand of increased substance/substrate(glucose) availability in unit time. That is, the heighted D-glucosefacilitated diffusion following maternal hypertonic D-glucose supplementis the multiplied product of attained V_(max)×the maximally recruitedcarriers all working at V_(max), the V_(max) being instantaneous intime. The said Vmax is highly significant in IUGR with markedlydiminished diastolic filling of the umbilical vessels, and only theshorter systolic time (of each cardiac cycle) providing for a better orany placental exchange.

Failure in the development of terminal villi and their capillaries whosecontribution for placental maternal-fetal exchange increasesexponentially during 31-36 weeks of gestation, could account for fetalIUGR in significant number of pregnancies so afflicted. This was foundto be associated with reduced umbilical artery end diastolic flow, whichis otherwise increased in normal pregnancy. Histometric support of thishypothesis is provided by the observations of reduced terminal villivolumes as well as reduced surface areas of the placentae of the IUGRfetuses (Tesdale F, 1984. Failure in the ‘fall of maternal peripheralvascular resistance’ usually by 16%, observed throughout in a normalpregnancy, can also be expected in this context.

The FIG. 1 A, the FIG. 1B, and the FIG. 1C schematically illustrate theeffect of exceeding substrate (D-glucose) concentration on the placentalcell mediated transport, namely facilitated diffusion involving cellmembrane/cytosolic substrate carriers that are present in surplus to berecruited as the substrate concentration (the D-glucose in thisinstance) demands. The FIG. 1 A schematically shows normal placenta (10)depicted by four circled units, (a hypothetical number chosen forschematic illustration, and so are all the other quantitative numeralsspecified in this paragraph) representing four terminal villi (shown bynumeral 12) that can transport carrier-bound substrate or glucosemolecules, a total of sixteen (as four molecules in four units) underphysiological glucose concentration in the blood. Some such substratemolecules are shown numbered as 14 in the drawing having complimentarybinding contacts with the carriers (22) The unbound glucose moleculesare shown with numeral 17 in the drawing. The villi units in the IUGRplacenta (18) (FIG. 1 B) can carry only eight carrier bound glucosemolecules (numbered as 20 in the drawing) due to only half the number(represented as two units) of terminal villi units (21), or half thesurface area/volume available for contact with maternal sinusoids, perunit time of fetal cardiac cycle. It has to be noted that the operativeglucose carriers (22) can be either located in the cell wall membrane orcan be intracellular, but are schematically represented as one circularpool. During maternal hypertonic glucose supplements (as in FIG. 1 C),due to exceeding number of glucose molecules (numbered as 24 in thedrawing) presented in the sinusoids, and as a result an instantaneouslyattained V_(max) (yet with the unchangeable surface area/volume of theterminal villi units of an IUGR placenta), sixteen molecules of glucose(some numbered as 26 in the drawing) are bound to the additionallyrecruited glucose carriers (28) that are always there in surplus in thecell unit (despite reduced number and reduced surface area of theterminal villi in IUGR), to be recruited by the manipulated factor ofsurplus glucose (24) in the maternal sinusoids.

Effects of Placental Insufficiency Other than Hypoglycemia—

Fetal hypoxia, hypercapnia, lactic acidosis, and impaired feto-maternalexchange across the placenta are the biochemical consequences for longconventionally linked to the primarily declined placental function, yetthis specification convincingly proves by available objective data thatthe therapeutic intervention of IV hypertonic glucose supplement in andby itself effectively relieves the said biochemical consequences. Suchobservation/deduction conforming to the needed ‘as a whole inquiry’carries enormous significance in dispelling the possible skepticismthat—glucose supplement might relieve fetal hypoglycemia, but the otherinvariable associations of placental insufficiency such as hypoxia andthe like are still detrimental to the fetal well-being, and hence theproposed treatment is of no consequence.’

The D-Glucose, the fittest fetal fuel—

There are operational mechanisms in pregnancy to minimize glucoseutilization by the mother, thereby making it available to the fetus,glucose being it's prime nutrient, intended by nature. Human PlacentalLactogen (HPL), a pregnancy hormone secreted by the placenta, andnormally present in the mother but not in the fetus, is believed to beblocking the peripheral uptake and utilization of D-glucose by maternaltissues, while also promoting the mobilization and the utilization offree fatty acids (FFA) by the mother for energy requirements. Fats andproteins are also transported across the placenta, but they play a majorrole only in anabolic function of rapid tissue accretion needed foroptimal fetal growth, or for targeted bodily functions, but not for thecatabolic energy-yielding purposes within the fetus. The scientificrationale why D-glucose is the chosen fetal fuel for the therapy, andnot any other major nutrients acclaimed as equal (the proteins), orsuperior (the lipids) in ‘food caloric value’ focuses on the nature'srationale itself (and hence this invention's) for it's selection as thefittest. Such biochemical derivation is very relevant to thisdiscussion, as other supplements if promoted as prime fetal nutrients(at the expense of glucose) are clearly detrimental, and may not beconsidered as potential fetal energy/ATP sources.

The major compromise that has direct bearing in fetaldemise/deterioration in the setting of fetal IUGR is undoubtedly linkedto fetal hypoglycemia and fetal hypoxia. GLUCOSE because of it'sdominant function in the ultimate catabolic oxidation via the ‘citricacid cycle’ is pivotal in generating ATP, the source of life and energy.Though OXYGEN (O₂) is breathed-in by all living organisms, and taken upby the fetus from the maternal source, ultimately it is the cellularrespiration and ‘oxidative phosphorylation’ via molecular oxygen withinthe mitochondria, the ‘power house’ organelles of the cell, that areultimately responsible for generating ATP, via the maneuvers of theD-glucose mediated ‘citric acid cycle’.

Accordingly, what happens at large at the organ level is ultimatelyreflected at the cellular and biochemical level and vice versa, andunderstanding such micro-functions of cell organelles as the ultimateATP generators to sustain life is the only clue to explore or search forany convincing relief to be sought for the significant fetal deficitssuch as hypoglycemia and hypoxia, while the placental pathology itselfmay not be alleviated. It necessitates the in-depth biochemicaldiscussion of the major (the carbohydrate, lipid, and protein), and someminor fetal metabolic pathways invariable for discovering what is yetundiscovered, or for dispelling legitimate concerns that may not byother means be explained, nor over ruled. The compelling motivation forsuch diligent exploration is the author inventor's successful case studyitself that proved that there is something intriguing that is yet to beexplored and found. What is found is truly intriguing as was thought(though some are universally known biochemical/biophysical facts underdifferent context), and is herein elaborated in the following sections.

The Carbohydrate Metabolism

The carbohydrates, characterized by a basic compact structural formulaC_((n)) H_((n)) O_((n)) (the carbon, hydrogen, and oxygen being presentin varying number n) are the aldehyde or ketone derivatives ofpolyhydric alcohols, existing either as isomeric straight chains or asstable 5 carbon (furanose) or 6 carbon (pyranose) ring structures. Theyare universally distributed in all living forms. In plants they aresynthesized as starch by the photosynthetic reaction between CO₂ (carbondioxide) and H₂O (water), and animals ultimately derive the requiredcarbohydrates primarily from plant sources, only insignificant amountsbeing synthesized in the animal body from the proteins and the lipids.The most interesting and foremost member of the class, the glucose, ahexose sugar (one having 6 carbon atoms) is represented in a compactchemical formula as C₆H₁₂O₆, and the H⁺ and O₂ present in the same ratioas that of water molecule may be noted, as the carbohydrates arewater-rich substrates, a property responsible for their bulk (comparedto the fats/lipids that are water-desiccated during their synthesis fromthe parent carbohydrates, as can be observed later in this discussion,and hence are acclaimed to carry higher energy in the same unit weight),and such structure representing the hydrogen-oxygen ratio of watermolecule can also be noted in the triose, tetrose, and pentose sugars.

The Carbohydrates are Classified as—1. Monosaccharides—they are carbohydrates that can not be furtherreduced to simpler forms. They comprise of trioses(ex.—dihydroxyacetone, the important intermediate of glycolysis),tetroses, pentoses (ex—the ribose sugars of DNA and RNA), and of hexoses(ex—glucose, fructose, and galactose), each containing 3, 4, 5 or of 6carbon units respectively. All dietary complex carbohydrates are brokendown, and absorbed into the body in simpler monosaccharide form, such asglucose.2. Disaccharides—they are made of 2 monosaccharide units (ex—sucrose andmaltose).3. Polysaccharides—they are made of more than 10 monosaccharide units(ex—starches, dextrins).

The major pathways of carbohydrate metabolism having substantiveclinical and biochemical significance, and relevant to this discussion,are—

-   -   1. The Glycolysis (the Embden-Meyerhof pathway),    -   2. The Krebs Citric Acid Cycle (or the tri-carboxylic acid        cycle), and    -   3. The Hexose Monophosphate (HMP) Shunt, or the Pentose        Phosphate Pathway (PPP).

The Pathway of Glycolysis (the Embden-Meyerhof Pathway)—

Glycolysis, the initiating pathway for the D-glucose metabolism, occursin the cytosol (the cytoplasm) of the cell, and is unique in that it canoccur either aerobically or anaerobically. It is also the maininitiating metabolic pathway of fructose, galactose, and also of theother carbohydrates derived from the diet. It is schematically shown inthe FIG. 2.

The Steps of Glycolysis are as Follows—

-   -   1. D-Glucose (1) is phosphorylated to glucose 6-phosphate (2),        an irreversible reaction, catalyzed by hexokinase (glucokinase),        using ATP in the presence of Mg²⁺.    -   2. Glucose 6-phosphate (2) is reversibly converted to fructose        6-phosphate (3) catalyzed by phosphohexose isomerase.    -   3. Fructose 6-phosphate (3) is further irreversibly        phosphorylated to fructose 1,6-biphosphate (4) through an enzyme        catalysis involving phosphofructokinase, in the presence of        Mg²⁺, also utilizing one molecule of ATP.    -   4. Fructose 1,6-biphosphate (4) (a 6-carbon moiety) is cleaved        by aldolase into two triose phosphates (3-carbon moieties)—the        glyceraldehyde 3-phosphate (5), and the dihydroxyacetone        phosphate (6). This is also a reversible reaction.    -   5. Glyceraldehyde 3-phosphate (5) and dihydroxyacetone phosphate        (6) are inter-convertible by the enzyme action of phosphotriose        isomerase. The inter-conversion is also reversible. However,        only glyceraldehyde 3-phosphate (5) can continue further into        the next step of glycolysis. The other isomeric form, the        dihydroxyacetone phosphate (6) is the important intermediate of        glycolysis that forms the link to the pathway of lipogenesis (7)        via formation of glycerol 3-phosphate (8), one molecules of        which incorporates 3 molecules of free fatty acids (FFA) (9) in        the formation of one molecule of triglyceride (TGD) (11).    -   6. Glyceraldehyde 3-phosphate (5) is reversibly oxidized to        1,3-bisphosphoglycerate (16) by the enzyme glyceraldehyde        3-phosphate dehydrogenase, a reaction that is dependent on NAD⁺        (13) (the nicotinic acid adenine dinucleotide). In this        reaction, the NAD⁺ (13) is reduced to NADH+H⁺ (15) (the        nicotinic acid adenine dinucleotide with hydrogen ion). This        reaction is significant, as the NADH+H⁺ (15) formed in the        reaction in turn transfers the reducing equivalents (the 2H⁺) to        the mitochondria (via the malate shuttle, shown in the FIG. 3,        to be described later) for the oxidative phosphorylation in the        respiratory chain. 2 of NADH+H⁺ (15) are produced during this        reaction, as all the reactions are duplicated due to two trioses        formed during step-4 above, and both separately continued        through further steps of glycolysis, in the form of        glyceraldehyde 3-phosphate (5).    -   7. 1,3-bisphosphoglycerate (16) transfers a high energy        phosphate group (˜{circle around (P)}) onto ADP (the adenosine        diphosphate) to form ATP, while itself is converted to        3-phosphoglycerate (19). This substrate level phosphorylation,        which is reversible, is catalyzed by phosphoglycerate kinase in        the presence of Mg²⁺. As two molecules of triose phosphates are        formed in step-4, two molecules of ATP are also generated at        this step per single molecule of glucose.    -   8. 3-Phosphoglycerate (19) is isomerized to 2-phosphoglycerate        (23) by the enzyme phosphoglycerate mutase.    -   9. 2-phosphoglycerate (23) is involved in a dehydration reaction        catalyzed by enolase to form phosphoenolpyruvate (25), in the        presence of Mg²⁺.    -   10. Phosphoenolpyruvate (25) then transfers a high energy        phosphate group onto ADP to generate ATP, while itself is        transformed to (enol) pyruvate (27). This is also a substrate        level phosphorylation catalyzed by the enzyme pyruvate kinase in        the presence of Mg²⁺. It has to be noted that 2 ATP are also        produced during this substrate level phosphorylation from 1        molecule of glucose. This reaction is irreversible.    -   11. (Enol) pyruvate (27) by a spontaneous nonenzymatic        isomerization is irreversibly converted to (keto) pyruvate (29),        or simply called pyruvate (29), the end product of glycolysis        under all aerobic conditions.

Evidently, 2 molecules of pyruvate (29) are produced from 1 molecule ofglucose (1) at the end of glycolysis in the cytosol, both to entercitric acid cycle (98) under aerobic conditions. The alternate pathwayof anaerobic glycolysis (involving lactate dehydrogenase) prevailing inhypoxic conditions, and depicted on the left of the step-6 (catalyzed bythe enzyme glyceraldehyde 3-phosphate dehydrogenase) of glycolysis, willbe detailed in a later section.

The Formation of Acetyl-CoA from Pyruvate—

The pyruvate formed in the cytosol is transported into themitochondrion. In the inner mitochondrial membrane, the pyruvate isoxidatively decorboxylated to acetyl-CoA (acetyl Co-enzyme A) (97) by amulti-enzyme complex, the ‘pyruvate dehydrogenase complex’. One moleculeof CO₂ is also generated in this step. This reaction is irreversible,and requires the presence of thiamine (the vitamin B₁), FAD (the flavinadenine dinucleotide, or the flavoprotein), NAD⁺, and lipoamide. It isclinically relevant to note that in states of thiamine deficiencypyruvate accumulates causing pyruvic acidosis, with the symptoms ofberi-beri. The requirement of thiamine is proportional to thecarbohydrate intake. In this reaction, NAD⁺ is reduced to NADH+H⁺, whichin turn transfers reducing equivalents (2H⁺ or protons) to the‘respiratory chain’ under aerobic conditions, producing 6 ATP from 2pyruvate molecules derived from 1 molecule of glucose. The formation ofacetyl-CoA (97) and CO₂, from the oxidation of pyruvate (29) within themitochondria, and the acetyl-CoA (97) so generated entering the citricacid cycle (98) are also illustrated in the FIG. 2.

The Krebs Citric Acid Cycle

The Krebs citric acid cycle or the tricarboxylic acid cycle (FIG. 4) isthe final common pathway for the catabolic aerobic oxidation of allmajor food stuffs, the carbohydrates, the proteins, and the lipids, thatare metabolized to either acetyl-CoA (83), or to the other intermediatesof the citric acid cycle (82), to be channeled into this lifesustaining, ATP generating final cyclic maneuver, the substrate foroxidative phosphorylation via the respiratory chain (FIG. 5). Theenzymes of the citric acid cycle (82) are located in the innermitochondrial membrane where the enzymes of the respiratory chain arealso found. The intermediates of citric acid cycle (82) also play avital anabolic role in lipogenesis (described in the following pages),gluconeogenesis, amino acid synthesis/interconversion viaα-ketoglutarate (91), and also in the synthesis of other specializedproducts like heme from succinyl-CoA (92) of the citric acid cycle.

The Krebs Citric Acid Cycle is Described as Below—

-   -   1. Acetyl-CoA (83) formed from pyruvate (85) interacts with        oxaloacetate (84) also derived from pyruvate (85) (by the        enzymatic action of pyruvate carboxylase), to form a        tricarboxylate, the citrate (87). This reaction is irreversible,        and is materialized by the enzyme citrate synthase. Only a small        quantity of oxaloacetate (84) is needed for the oxidation of        large quantity of acetyl-CoA (83). It is for the reason that in        this cyclic pathway, oxaloacetate (84) is regenerated during        each turn of the cycle, whereas the acetyl-CoA needs to be        continuously supplied from pyruvate (85), generated as the end        product of glycolysis.    -   2. Citrate (87) is isomerized first to cis-aconitate (88) and        then to isocitrate (89) by the enzyme aconitase. Citrate (87) is        one of the two intermediates of citric acid cycle that can        freely get out of the mitochondria, so as to form the anabolic        link to extra-mitochondrial fatty acid synthesis. In the cytosol        of the tissues specializing lipogenesis, it reforms oxaloacetate        and acetyl-CoA, the latter being the integral building block for        the fatty acid synthesis    -   3. Isocitrate (89) is dehydrogenated by isocitrate dehydrogenase        to form oxalosuccinate (90), and during this process the NAD⁺ is        reduced to NADH+H⁺. The oxalosuccinate (90) remains enzyme        bound, but subsequently is decarboxylated to α-ketoglutarate        (91) in the presence of Mg²⁺ or Mn²⁺ ions, and during this        process one molecule of CO₂ is also produced. 1 NADH+H⁺ produced        during the reaction generates 3 ATP via the respiratory chain.    -   4. α-ketoglutarate (91) is decarboxylated by a multienzyme        complex, the α-ketoglutarate dehydrogenase complex resulting in        the formation of succinyl-CoA (92). This enzyme complex is        similar to pyruvate dehydrogenase complex that oxidizes (keto)        pyruvate (85) to acetyl-CoA (83). Hence in this reaction similar        co-factors like thiamine, lipoate, FAD, NAD⁺ and CoA are        required. One molecule of CO₂ is similarly liberated in this        reaction. 1 NADH+H⁺ produced generates 3 ATP.    -   5. Succinyl-CoA (92) is converted into succinate (93), in the        presence of Mg²⁺ through the enzymatic action of succinate        thiokinase (succinate synthase). ADP is also converted into ATP        during this reaction, a single example of substrate level        phosphorylation in the citric acid cycle.    -   6. Succinate (93) by a dehydrogenation process forms fumarate        (94) by the enzyme succinate dehydrogenase. FAD is bound to the        enzyme and is reduced to FADH₂ (the reduced form of favin        adenine dinucleotide) which directly transfers reducing        equivalents to ubiquinone of the respiratory chain to reform        FAD. It can be noted at this point that only 2 ATP are produced        during this step by the flavoprotein.    -   7. Fumarate (94) by condensation with water forms malate (95),        catalyzed by the enzyme fumarase or fumarate hydratase.    -   8. Malate (95) is converted in this last step of the citric acid        cycle to one of the parent compounds, the oxaloacetate (84), by        malate dehydrogenase in a NAD⁺ dependent reaction that also        generates NADH+H⁺. 3 ATP are produced during this step. This        reaction is significant through it's involvement in malate        shuttle (FIG. 3), wherein as mentioned before, the reducing        equivalents (H⁺) from the continuous extra-mitochondrial        formation of NADH+H⁺ (via glycolysis) are transported into the        mitochondria as malate. It is for the reason that the        mitochondria, the sole substrate for the oxidative        phosphorylation are impermeable to cytosolic NADH+H⁺.

It can be noted that during combustion of 1 molecule of D-glucose (86),a total of 6CO₂ molecules are liberated: (a) 2 CO₂ during the formationof 2 acetyl-CoA (83) molecules from 2 pyruvate (85) molecules, and (b) 4CO₂ during the citric acid cycle (also involving 2 cycles).

The Generation of High Energy Phosphate by Oxidative Phosphorylation Viathe Respiratory Chain—

The outlines of the scheme of oxidative phosphorylation are illustratedin the FIG. 5. To understand this process of biologic oxidation thatyields high energy ATP in all living cells, it is essential tounderstand/define the biochemical processes of ‘oxidation’ and‘reduction’.

Oxidation is the addition of oxygen to, or removal of hydrogen from anelement or compound. Essentially, it is removal of electrons. Reductionis the addition of hydrogen to or removal of oxygen from an element orcompound. Essentially, it is gain of electrons. Accordingly, manyreactions of biologic oxidation can take place via dehydrogenation(through dehydrogenase enzyme complexes that can not use oxygen as ahydrogen acceptor) even without the participation of molecular oxygen.

In the aerobic organisms, during the oxidative phosphorylation thattakes place inside the respiratory chain (33) of the mitochondria, theoxidation is tightly coupled to phosphorylation (Mayes P A) to generatethe high energy intermediate, the ATP. Most of such energy to beliberated during the oxidation (the catabolism) of carbohydrates,proteins, and of fats is made available within the ‘respiratory chain’of the mitochondrial matrix as reducing equivalents (2H⁺ or theelectrons of NADH+H⁺ or FADH₂) that are collected and are transportedfor their final interaction with molecular oxygen (½ O₂) (81) to formwater (H₂O) (77). The respiratory chain (33) contains a number of redoxcarriers, arranged in sequence as—the NAD⁺ linked dehydrogenase, theflavoprotein, the ubiquinone, and the ‘cytochromes’ that are cytochromeb (cyt b), cytochrome c₁ (cyt c₁), cytochrome c (cyt c), and cytochromeaa₃ (cyt aa₃), arranged in that order. Each of the respiratory chain(33) complexes act as a ‘proton pump’. According to Mitchell'schemiosmotic theory, through the process of oxidation in the respiratorychain, energy is derived that is used for the translocation of protons(H⁺) to the exterior of mitochondrial inner membrane. The mitochondrialmembrane being generally impermeable to ions, especially protons, (theFADH₂) generated in the reaction catalyzed by succinate dehydrogenase(41) produces only 2 ATP. When either 1 NADH+H⁺ or 1 FADH₂ participatesin the oxidative phosphorylation, ½O₂ (81) is utilized to interact withthe reducing equivalent (the 2H⁺) to form water (H₂O) (77), and alsosimultaneously 3 or 2 ATP respectively.

A total of 6O₂ is required to completely oxidize 1 molecule of D-glucoseto produce 38 ATP, as can be observed in the following table-1. Thisfactual knowledge is important in understanding the ‘best economics’ ofglucose as the fetal fuel to generate ATP, and the frugality of thishexose sugar is never found during the catabolic use of proteins or oflipids, in terms of oxygen expended during similar gain of ATP for thefetus deemed to thrive in relatively hypoxic states in utero. The rathercomplicated process of oxidative phosphorylation is only brieflyoutlined here, the in-depth enumeration of which is beyond the scope ofthis discussion, but can be found in any standard text book ofbiochemistry.

Anaerobiosis and Lactic Acidosis—

Under anaerobic conditions (111), the end product of glycolysis islactate (113) that is derived from pyruvate (29). The scheme ofanaerobiosis or anaerobic glycolysis (111) is also shown in FIG. 2 onthe left side of the reaction catalyzed by glyceraldehyde 3-phosphatedehydrogenase. The reaction involving anaerobic glycolysis (111) iscatalyzed by lactate dehydrogenase, when the NADH+H⁺ (15) is oxidized toNAD⁺ (13) during the process, while pyruvate (29) itself is reduced tolactate (113). As pyruvate (29) is not the end product, the citric acidcycle (98) is not effectuated in the anaerobic conditions (111).However, glycolysis can be continued even during hypoxic/anoxic states,but with the continued availability of glucose (1), when NADH+H⁺ (15)generated in step-6 of glycolysis (described in the earlier section), isused to reduce pyruvate (29) to lactate (113) (FIG. 2), and the NAD⁺(13) so generated in the step involving lactate dehydrogenase can befurther used for the step-6 of glycolysis to proceed, so that only 2 ATPare generated from 1 molecule of D-glucose (1) at the substrate level,the their accumulation outside the mitochondrial inner membrane createsan electrochemical potential difference across the membrane that is usedto drive the ATP synthase to form ATP during the availability of ADP andPi (the inorganic phosphate or the PO₄ ⁻). ATP synthase is located inthe adjacent inner mitochondrial membrane.

The inner mitochondrial transporter system also has phosphatetransporter (that allows the transport of inorganic phosphate thatpasses readily as H₂PO₄ ⁻ ion) that exists in combination with adeninenucleotide (the ADP and ATP) transporter. In the so called process of‘oxidative phosphorylation’ the molecular oxygen (81) derived from therespiration of the organism in fact makes no structural contribution toATP, and actually forms H₂O (77) (in the final chemical reaction of‘oxidation’ within the respiratory chain, 33), combining with 2H⁺ ofNADH+H⁺ or FADH₂. The phosphate group (PO₄ ⁻) added to ADP is whollyderived from H₂PO₄ ⁻ (the dihydrogen phosphate ion entering the innermitochondrial membrane through it's transporter). It can be shown in asimplified schematic form, as below—

The merging into the Krebs citric acid cycle, of proteins (amino acids)(of groups 43, 47, 53, 55, 61, and 65) and lipids (the free fatty acids)(49) as acetyl-CoA (51), or as the citric acid cycle (31) intermediatesfor their final catabolic disposal to generate substantial amounts ofATP, is also shown in the FIG. 5. The amino acids of—group 43 producepyruvate (45); group 47 produce acetyl-CoA (51); group 53 producefumarate (79); group 55 produce glutamate (57) and then α-ketoglutarate(59); group 61 produce succinyl-CoA (63). Aspergine (65) producesoxaloacetatae (67). In the respiratory chain (33), as mentioned in theforegoing, the oxidative phosphorylation of NADH+H⁺ generated in thereactions catalyzed by isocitrate dehydrogenase (35), α-ketoglutaratedehydrogenase complex (37), and malate dehydrogenase (39) produces 3ATP, whereas the flavoprotein

TABLE 1 The generation of ATP via D-glucose catabolism Metabolic numberpathway mode of ATP of ATP involved enzyme catalyst production formedGlycolysis Glyceraldehyde oxidation of 2 NADH 6 3-phosphate via resp.chain dehydrogenase Phosphoglycerate substrate level 2 kinasephosphorylation Pyruvate kinase substrate level 2 phosphorylation TotalATP gain 10 ATP used through ‘hexokinase’ and −2 ‘phosphofructokinase’Net ATP gain 8 Formation pyruvate oxidation of 2 NADH 6 of acetyl-CoAdehydrogenase via resp. chain Citric acid Isocitrate oxidation of 2 NADH6 cycle dehydrogenase via resp. chain α-ketoglutarate oxidation of 2NADH 6 dehydrogenase via resp. chain Succinate thiokinase substratelevel 2 phosphorylation Succinate oxidation of 2 FAD₂ 4 dehydrogenasevia resp. chain Malate dehydrogenase oxidation of 2 NADH 6 viaresp.chain Net ATP gain 30 Total ATP per molecule of glucose under 38aerobic conditions Total ATP per molecule of glucose under 2 anaerobicconditions2 NADH+H⁺ (15) of step-6 of glycolysis, precluded from being used in themitochondrial oxidative phosphorylation (115) of the respiratory chain(shown on the right side of the step catalyzed by glyceraldehyde3-phosphate dehydrogenase) to otherwise produce an additional 6 ATP (3ATP from 1 NADH+H⁺). It may be understood that only one of the alternatepathways, either the one depicted in the left (the anaerobicglycolysis), or the one depicted on the right (the aerobic glycolysis)of the step-6 catalyzed by glyceraldehyde 3-phosphate dehydrogenase inFIG. 2, is materialized at any time.

With the availability of glucose (1), though glycolysis can be continuedindefinitely even in hypoxic/anoxic conditions, it is not withoutadverse effects on the fetus neonate, as it can lead to lactic acidemiawith the consumption of fetal base reserves, a situation only rescued byoxygen.

The Malate Shuttle—

The Malate shuttle (76) (illustrated in FIG. 3, part of it shown as thebottom half of the ovoid maneuver) is very important to understand themany facets of carbohydrate metabolism, as essentially the benefits ofaerobic glycolysis can not be reaped without this ongoing maneuver. TheNADH+H⁺ (30) is continuously formed in the cytosol through the reactioninvolving glyceraldehyde 3-phosphate dehydrogenase (32) of glycolysis(glycolytic pathway) (34). However, the mitochondrial membrane (64) isimpermeable to NADH+H⁺ (30), and for the needed oxidativephosphorylation of the reducing equivalents, their transfer through themitochondrial membrane (64) requires substrate pairs on each side of themembrane barrier, and is achieved via glycerophosphate shuttle, or themalate shuttle (76). The latter being more prevalent, and being morepertinent to the present discussion, for the needed comprehension alsoof a very important subject matter of lipogenesis (involved in rapidfetal brain neurogenesis) to be discussed in the subsequent sections, itneeds elaboration for it's precise understanding.

-   -   1. Essentially in this shuttle, oxaloacetate (38) (of citric        acid cycle, 74 shown in the FIG. 3, as the upper half of the        ovoid maneuver) gets out of the mitochondria, and comes in as        malate (56), and hence the originator of the shuttle is        oxaloacetate (38) that needs to be transported out from the        mitochondria. The complexity of the shuttle is due to the fact        that oxaloacetate (38) can not penetrate the mitochondrial        membrane (64). It must react with glutamate (40) that is        transaminated (by the mitochondrial transaminase) to aspartate        (42), while itself is changed to α-ketoglutarate (44) in the        process, that can easily penetrate mitochondrial barrier It can        be noted that α-ketoglutarate and citrate are the only two        intermediates of citric acid cycle that can get out into the        cytosol through the mitochondrial barrier, whereas malate can        come in, in exchange with either, however involving separate and        specific transporters for each.    -   2. The α-ketoglutarate (44) is transported out through        mitochondrial membrane (64) via the ketoglutarate transporter        (KGT) (46) (the KGT can be noted in FIG. 3 as a rectangular        solid area within the mitochondrial membrane, 64), whereas the        aspartate (42) is transported out through the        glutamate/aspartate transporter (GAT) (48) (the GAT can be noted        in FIG. 3 as a hatched rectangular area within the mitochondrial        membrane, 64).    -   3. Within the cytosol (70) further interaction between the two        i.e the α-ketoglutarate (44) and aspartate (42) reconstitutes        oxaloacetate (50) and glutamate (52), in a reaction involving        the cytosolic transaminase (54).    -   4. The regenerated oxaloacetate (50) in the cytosol (70)        interacts with NADH+H⁺ (30) that is continuously generated via        glycolysis (34) to produce malate (56) and NAD⁺ (58), the        reaction being catalyzed by the cytosolic isoenzyme, the malate        dehydrogenase (60). The reaction is as follows—

-   -   5. The malate (56) can pass into the mitochondrion, via the        ketoglutarate transporter (KGT) (46) in exchange with more of        α-ketoglutarate (44) coming out of the mitochondrion, for the        shuttle to be on-going.    -   6. The glutamate (52) reenters the mitochondrion through        glutamate/aspartate transporter (GAT) (48) so as to continue the        shuttle.    -   7. Within the mitochondrion, the malate (56) interacts with NAD⁺        (62) to regenerate oxaloacetate (38) and NADH+H⁺ (66) (that        forms 3 ATP), catalyzed by mitochondrial malate dehydrogenase        (68) in the usual manner as the last step of the citric acid        cycle (74), how ever, the ‘reducing equivalents’ (of NADH+H⁺)        (66) evidently are transferred from the cytosol (70) in the form        of malate (56) through the shuttle, and hence the credit of 3        ATP acquired is normally accounted to glycolysis (34), and it is        obviously in addition to the 3 ATP gained through malate (72)        formed also through full revolution of the citric acid cycle        (74). As normally the malate (56) of malate shuttle merges into        the citric acid cycle, and can be imperceptible from malate (72)        formed as the end product of the full revolution of the citric        acid cycle itself, both the products (56, 72) are shown        connected through a bidirectional arrow (FIG. 3) through which        the malate of either pathway is implied to terminate into a        common mitochondrial malate pool.

It can be noted that the steps of forming α-ketoglutarate (44) fromoxaloacetate (38) via malate shuttle (76) are very different from thesteps involved for the formation of the same via the citric acid cycle(FIG. 4).

The Hexose Monophosphate Shunt (HMP Shunt) or the Pentose PhosphatePathway—

The pentose phosphate path way or HMP shunt is a specialized route ofglucose metabolism, as it mainly has anabolic significance, andaccordingly does not generate ATP. It has two major synthetic functions—

1. Formation (from NADP⁺) of NADPH+H⁺ (the phosphorylated form ofnicotinic acid adenine dinucleotide and the hydrogen ions) thatparticipates as a hydrogen donor during the synthesis of free fattyacids (FFA), and of steroids.2. Formation of D-riboses, the pentose sugars vital for the synthesis ofnucleotides, and the nucleic acids, the DNA and the RNA(deoxyribonucleic acid and the ribonucleic acid).

The pentose phosphate pathway or the HMP shunt (HMPS) is a more complexpath way than glycolysis. 3 molecules of glucose give rise to 3molecules of ribose sugars, and it can be noted also that 3 molecules ofCO₂ are produced in this process. The NADP⁺ (the phosphorylated form ofnicotinic acid adenine dinucleotide) is used in the path way as thehydrogen acceptor. The process is extra-mitochondrial and is more activein tissues predominantly engaged in the synthesis of free fatty acids,and of steroids. No oxygen is used in the pentose phosphate path way, asobviously the reducing equivalents (the 2H⁺) acquired by the coenzymeNADP⁺ via the path way are meant to be used for the anabolic synthesesof free fatty acids, steroids etc.

The Physiological Significance of Lipids and Proteins—

The significance of glucose as the predominant fetal fuel for thereasons of it's high ATP yield, and accordingly as the chosen fetalnutritional supplement in the treatment modalities of this invention canbe best appreciated only in the light of the discussion of the lipid andof the protein metabolic path ways within the fetal body, the latterpath way most surprisingly expending oxygen/ATP in a rather extravagantmanner even before it's end products gaining some similar number of ATPas the other merging metabolic end products, via the ultimate steps ofthe landmark meeting point, the citric acid cycle. This knowledge,acquired in the light of biochemical and mathematicalevaluations/equations is needed for an understanding that is reliableand objective.

The Lipid Metabolism

LIPIDS in their SIMPLE form are heterogeneous group of compounds thatare essentially esters of fatty acids with various alcohols, the fattyacid straight chain in natural form existing either as a saturated orunsaturated aliphatic carboxylic acid.

The lipids as a class have the common property of being insoluble inwater, and soluble in solvents like chloroform and ether. They comprisethe major constituents of human diet, and are significant for their highenergy value per unit volume/weight, and accordingly, are efficientenergy store-houses of the body, to be used on demand. They areimportant for their containment of fat soluble vitamins also. The lipidscomprise the following major classes:

Simple lipids,Complex lipids,Precursor or derived lipids, andNeutral lipids.1. Simple lipids—these are esters of saturated or unsaturated fattyacids with various alcohols (ex—glycerol, sphigosine). The acetic acid,palmitic acid, stearic acid etc. are the examples of saturated fattyacids, whereas linoleic, linolenic, arachidonic, and ω3 hexaenoic acidsare examples of unsaturated fatty acids. Palmitic acid, and ω3 hexaenoicacids (that ultimately form complex phospholipids in the brain startingfrom chain elongation of palmitic acid) are synthesized in humans,whereas the linoleic, linolenic, and the arachidonic acids are essentialfatty acids that are to be primarily derived from food, either of plantor of animal sources.2. Complex lipids—these are esters of fatty acids and alcohol, alsocontaining additional groups like a phosphoric acid residue, acarbohydrate, or a protein, as in the following groups—

-   -   a. Phospholipids—are lipids containing an ESTER of fatty acid        and alcohol, and additionally, a phosphoric acid residue.    -   b. Glycolipids—are lipids also containing an ESTER of fatty acid        and alcohol, and instead of a phosphoric acid residue, they        contain a carbohydrate (galactose, or less often glucose).    -   c. Other complex lipids—examples are aminolipids, lipoproteins,        and sulfur containing sulfolipids.        3. Precursors or derived lipids—the precursor lipids include        fatty acids, glycerol, and other alcohols (the precursors of        lipids, as the name imply). The derived lipids include steroids,        hormones, lipid soluble vitamins, fatty aldehydes, and ketone        bodies.        4. Neutral lipids—these are so named as they are uncharged, and        exemplify acylglycerols (the mono-, di-, or tri-glycerides),        cholesterol, and the cholesterol esters.

The Biosynthesis of Free Fatty Acids (FFA)

This discussion is important as the lipogenesis is an integral part ofthe developing brain (and the thermoregulatory subcutaneous adiposetissue), and it is critical to know how best this vital organ can bespared from growth restriction by obviating the need for otherwiseexcessive amount of molecular oxygen. As the 16 carbon atom fatty acid,the palmitic acid is the predominantly synthesized fatty acid in thefetus (that can be further elongated to a fatty acid with 24 carbonatoms chain in certain tissues, as in the brain), it is chosen as theprototype example for the present discussion of fetal fatty acidbiosynthesis.

It was noted in the foregoing discussion of the carbohydrate metabolism(under subsection-2 of the citric acid cycle) that acetyl-CoA is anintermediate that is formed from pyruvate after it's entry into themitochondria, and that it is the building block of the fatty acids. Thelipid anabolic process starts at the outset as the glucose catabolicprocess (the glycolysis) that expends O₂, and also generates ATP in thatprocess.

It has to be noted that though acetyl-CoA, the building block of thefree fatty acids is generated within the mitochondria from pyruvate, thesynthesis of palmitic acid (and all fatty acids) is extra-mitochondrial(cytosolic).

The Biosynthesis of the Free Fatty Acids (FFA), with Palmitic AcidChosen as the Prototype for Discussion, is as Below—1. Acetyl-CoA (the building block of fatty acids) formed in themitochondria can not penetrate the mitochondrial barrier to enter thecytosol, and hence has to form citrate via the citric acid cycle, andthe citrate so generated can get out into the cytosol (in exchange withmalate) through the mitochondrially located citrate (or thetricarboxylate) transporter.2. Citrate, within the cytosol, is cleaved to acetyl-CoA andoxaloacetate (FIG. 2), a step that uses ATP, and is catalyzed by ATPcitrate lyase.3. Acetyl-CoA in the cytosol is carboxylated to melonyl-CoA, in thepresence of ATP by acetyl-CoA carboxylase. This reaction requires HCO3⁻(as the source of CO₂), biotin, a B-complex factor and manganese.

4. Melonyl-CoA condenses with one more acetyl unit, when CO₂ added inthe previous step is liberated. As this reaction takes place while thereacting molecules are still attached to the surface of an enzymecomplex, the fatty acid synthase multienzyme complex (E), it can bewritten as—

The product of this reaction is an enzyme bound acid with 4 carbonatoms, with a keto group (the CO group, with a double bond) beinglocated in β position. The carbon atoms are numbered from carboxyl (CO)carbon (the number 1). The adjacent carbon atoms, numbered 2, 3, and 4are also referred as α, β, and γ carbon atoms. The fatty acid groupafter it is evolved from the basic acetic group of the first member ofthe fatty acid series, the acetic acid (CH3-COOH), is referred to as anacyl group.

5. Reduction of β-keto group of aceto acetyl enzyme (3-keto acyl enzyme)by 2 NADPH+H⁺ catalyzed by 3-keto acyl reductase, gives rise to anenzyme bound 4-carbon acyl enzyme or 4 carbon butyryl enzyme which is asaturated enzyme bound fatty acid (butyric acid is the third member ofthe fatty acid series, containing 4 carbon atoms).

NADPH+H⁺ is readily available as the by-product of HMP shunt that iscytosolic also. HMP shunt (HMPS) is highly active in most of the fetaltissues, including the placenta, due to the function through the shunt,of production of ribose sugars (needed for the DNA and RNA, essentialfor fetal/placental cell replication). The carbohydrate oxidativereactions of HMPS reduces NADP⁺ to NADPH+H⁺ that is the main source ofhydrogen required for the reductive synthesis of fatty acids, as in caseof palmitic acid, a total of 28H⁺ ions are added through it'sbiosynthesis, via the NADPH+H⁺.

6. In a reaction similar to reaction 4 above, another melonyl unit isadded to the carboxyl end of the 4 carbon butyryl enzyme to generate a 6carbon 3-ketoacyl enzyme that is still enzyme bound. One molecule of CO₂is also liberated in the process in a similar manner.

The product of the reaction can be named as 3-keto caproyl enzyme(caproic acid is the fifth member of fatty acid series containing 6carbon units).

7. The new 6 carbon 3-keto acyl enzyme or 3-keto capryol enzyme is thenreduced to the corresponding 6 carbon saturated fatty acid, the 6 carbonacyl enzyme or caproyl enzyme, by 2 NADPH+H⁺ through the enzyme3-ketoacyl reductase in a reaction similar to reaction 5 above (alsoinvolving similarly named enzyme), as follows—

8. In the next step there will be again addition of melonyl unit toelongate the 6 carbon acyl enzyme to 8 carbon 3-keto acyl enzyme. Suchrepetitive and alternating additions of melonyl enzyme and then the 2H⁺of NADPH+H⁺ to first produce a 3-keto acyl enzyme, and then acorresponding saturated fatty acid enzyme respectively, result in theproduction of 16 carbon Palmitic acid through chain elongation by2-carbon addition, followed by 2H⁺ addition each time. The fatty acid(the palmitic acid) so formed is still enzyme bound, but splits off atthe end, as free 16 carbon palmitic acid: CH₃—(CH₂)₁₄—COOH. The sequencecan be stated as: the addition of 2 carbon units by melonyl-CoA to thecarboxyl end of the fatty acid chain with formation also of a 3 ketogroup, followed by reduction of the 3 keto group with 2H⁺ of 2 NADPH+H⁺.

The summated equation of the biosynthesis of palmitic acid fromacetyl-CoA and the melonyl-CoA can be shown as follows—

It can be understood that a total of 8 acetyl-CoA units, or 4 glucosemolecules are required in the biosynthesis of 1 molecule of palmiticacid.

Coming back to reactions 1 and 2 of palmitic acid synthesis, it wasstated that the citrate (99) gets out of mitochondria into the cytosol,and within the cytosol, it is cleaved to acetyl-CoA (105) andoxaloacetate (107) (FIG. 2). The oxaloacetate (107) generated in thecytosol reacts with NADH+H⁺ (15) (that is continually produced throughglycolysis) to form malate (109) which gets into the mitochondria inexchange with more of citrate (99) coming out, for the furthercontinuation of free fatty acid synthesis/lipogenesis (238).

FIG. 2 also shows triglyceride (TGD) (11) formation from glycerol3-phosphate (8), derived from the dihydroxyacetone phosphate (6) ofglycolysis, by the incorporation of free fatty acids (9).

The β-Oxidation of Lipids—

Fatty acid catabolism by oxidation, otherwise called as β-oxidation,like the citric acid cycle, is mitochondrial, and utilizes NAD⁺ and FADas coenzymes, and aerobically generates ATP via the mitochondrialrespiratory chain. Compared to D-glucose oxidation via glycolysis, fattyacid oxidation is a more oxygen consuming process, in terms of similarATP gain. The end products of β-oxidation of fatty acids are multipleunits of acetyl-CoA, destined to enter citric acid cycle to besubsequently catabolized in a similar manner as the acetyl-CoA moleculederived from glucose itself (or from any other source that merges intothe cycle). Just as the β carbon unit (3 carbon unit from the carboxylend) of the growing fatty acid chain was reduced during fatty acidsynthesis as described in the foregoing section, the β carbon unit ofthe fatty acid chain is oxidized in successive steps during thisprocess, to cleave an acetyl-CoA unit each time. The fatty acids bytheir high yield of acetyl CoA, are enormous sources of energy comparedto similar unit volume or weight of protein or carbohydrate, asvirtually fatty acid synthesis is a ‘desiccative process’ (of the parentglucose molecule) that eliminates water as shown in reactions 5 and 7 ofit's synthesis from the water-rich carbohydrate precursors. Make note ofthe addition of 1 molecule of water (that was earlier lost in thesynthesis) in reaction-3 below, as each molecule of acetyl CoA iscleaved. The β-oxidation of palmitic acid, the chosen prototype of thegroup, is described in the following discussion.

1. The fatty acid in the cytosol is first activated to an active fattyacid or acyl-CoA (or the palmityl-CoA) by acyl-CoA synthetase located inthe outer mitochondrial membrane—a reaction that requires ATP, which isreduced to AMP and PPi.2. Within the mitochondrial matrix two carbon units at a time arecleaved from the acyl-CoA molecule, starting at the carboxyl end. In thefollowing reactions the compact formula of the 16 carbon unit palmiticacid, CH₃—(CH₂)₁₄—COOH is shown as:

CH₃—(CH₂)₁₂—CH₂—CH₂—COOH

with two of it's CH₂ groups shown as discrete α and β carbon groups, tohigh-light the reactions involving these groups.3. The first step within the mitochondria is the oxidative removal oftwo hydrogen atoms from the 2 (α) and 3 (β) carbon units of the acyl-CoAthrough the enzymatic action of acyl-CoA dehydrogenase in the presenceof the coenzymes FAD (that is reduced to FADH₂), and NAD⁺ (that isreduced to NADH+H⁺), with also an addition of 1 molecule of water. Theoxidative phosphorylation of FADH₂ via the respiratory chain yields 2ATP, whereas that of NADH+H⁺ yields 3 ATP (with a total gain of 5 ATP),each reduced co-enzyme using ½O₂ (and a total of 1O₂) in the process.The reaction cleaves 1 molecule of acetyl-CoA from the fatty acid chain.

It has to be noted that in the below specified equation, it is thehighlighted (in bold print) third or the β-carbon unit of the 16 carbonacyl-CoA that is oxidized by the oxygen of the water molecule (theβ-oxidation) in a series of steps. To start with, the α and β groupsthat are the 2 and 3 carbon units (CH₂—CH₂) respectively, are oxidizedto CH═CH by FAD. Then in a reaction involving H₂O, NAD⁺ and CoA—SH, theyare transformed to CO—CH₃ following which the 1 and 2 carbon units ofthe fatty acid chain (the 1 carbon unit remaining as carboxyl carbon CO,but the second α-carbon unit CH₂ has been changed earliest to CH₃) arecleaved to form acetyl-CoA, while the β-carbon will be forming thecarboxyl carbon CO of the new fatty acid chain. The FADH₂ and NADH+H⁺are formed at the end of these reactions. The summated overall reactionis as shown below—

The cleavage of the subsequent molecules of acetyl-CoA from theremaining 14 carbon unit fatty acid chain (the acyl-CoA) can be shown asin the following equation. In this equation, the compact formula of the14 carbon atom acyl-CoA of above reaction is again shown with 2 of it'sCH₂ groups as discrete α and β groups, to clarify the chemical actioninvolved in these groups.

The oxidative process involving the α- and the β-carbon units (the 2 and3 carbon units) are similar, as was summated for the foregoing overallreaction.

In the reaction described above, one more molecule of water is consumed,and the β carbon unit of the fatty acid becomes the carboxyl carbon unitof the new acid, containing 12 carbon units, while the second moleculeof acetyl-CoA is cleaved. Repetition of the sequence results in thecleavage of the whole fatty acid chain into units of acetyl-CoA. In thecase of palmitic acid, the sequence is repeated 7 times, to yield 8molecules of acetyl-CoA, and 35 ATP (7×5), with the consumption of 7O₂and 2 high energy phosphates, the latter used for the initial activationof fatty acid. There is a net result of 33 ATP during the completecatabolic β-oxidation of palmitic acid to 8 units of acetyl-CoA.

The Comparison of Oxygen Consumption Vs. ATP Yield, During Glycolysisand β-Oxidation—

The consumption of oxygen, and yield of ATP during β oxidation can becompared to glycolysis (when 4 glucose molecules are spent), for similaryield of 8 acetyl-CoA, as shown below—

Oxidation of 4 molecules of D-glucose 8 acetyl-CoA 8 O₂ 56 ATP βoxidation of palmitate 8 acetyl-CoA 7 O₂ 33 ATP

As per the above, via glycolysis, 1O₂ produces 7 ATP, whereas via betaoxidation only 4.7 ATP are produced. That is, via glycolysis, the 7 ATPgenerated consuming 1O₂, are generating 2.3 more ATP compared to betaoxidation, when similar amount of oxygen is expended. It is significantthat per 100 ATP so produced, the glycolytic pathway of D-glucose isgenerating 32. 85 more ATP, or the ATP yield via glycolysis is 32. 85%more, compared to beta oxidation. Evidently, 32.85% (⅓rd ofrequirements) is also the equivalent amount of O₂ salvage, or reducedoxygen requirement via the glycolytic path way of D-glucose.

Starting as the size of a single cell ovum or a fertilized egg, andattaining in-utero of the size of a full term fetus of 3.5 kg or more in280 days, nothing in nature and in health can surpass the growthpotential of the developing fetus. For such unsurpassed growth, Oxygenis as valuable fetal currency as the food sources it can consume in arelatively hypoxic uterine habitat. With 32.85% excess of energy (ATP)provisions (or 32.85% of reduced O₂ expenditure, compared to the ‘mostsuperior lipids’ of the food group) in terms of food energy yield vs.oxygen spent, glucose is but the most fitting fuel of the fetus duringit's in-utero stay through ten lunar months.

Why Less Oxygen is Needed when Carbohydrates are Metabolized—

It had been discussed that during glycolysis-citric acid cycle, when 1molecule of D-glucose is metabolized, 6O₂ are used, and also 6CO₂ areproduced. It makes the RQ (the respiratory quotient) ofD-glucose/carbohydrates as 1. RQ is the ratio of the number of CO₂molecules produced, and the number of O₂ molecules consumed (CO₂/O₂)during a metabolic process in an unit time. When fats are metabolizedthe RQ falls to 0.7. It is because of the fact that in the carbohydratemolecule there is enough oxygen present to oxidize the hydrogen presentwithin the molecule to produce water (H₂O), and hence oxygen fromextrinsic sources is needed only to oxidize the carbon (to produce CO₂)present within the molecule. It was earlier noted how all thecarbohydrates—the trioses, tetroses, pentoses, and the hexoses containH⁺ and O₂ in the same ratio as that of the water molecule (it ishigh-lighted in the compact formula of glucose below).

When fat is combusted the oxygen present within is not sufficient sothat extrinsic oxygen is needed to oxidize both it's hydrogen and carbonatoms (Chatterjee CC).

The RQ is exemplified below as in the metabolic break down of glucose,the prototype carbohydrate, and tristearin (a triglyceride composed of 1molecule of glycerol, and 3 of stearic acid) taken as the prototypelipid.

C₆H₁₂O₆+6O₂→6CO₂+6H₂O; RQ: 6CO₂/6O₂=1 Glucose

2C₃H₅(C₁₈H₃₅O₂)₃+163O₂→114CO₂+110H₂O; RQ: 114CO₂/163O₂=0.7 Tristearin

As can be seen in the above equations, 6 molecules of O₂ are used in thecombustion of glucose to produce 6CO₂, and the 6H₂O molecules liberatedwere already present within the glucose molecule as high-lighted,whereas for the combustion of 2 molecules of tristearin, 163 moleculesof O₂ are required to oxidize 220H⁺ to produce 110H₂O, and also tooxidize 114 carbon atoms to produce 114 CO₂, as the O₂ present withinthe 2 molecules are only 12.

The Keto Acidosis—

The above discussion of fatty acid beta oxidation clarifies that whenfats are utilized as the source of energy, the acetyl-CoA are generatedin enormous numbers. They are destined to merge into citric acid cyclefor their further catabolic disposal. In times of diminished glucoseavailability as in IUGR, due to lack of sufficient amounts ofoxaloacetate, that has to be derived from glucose, acetyl-CoA can notmerge into citric acid cycle. It's further fate is to form ketonebodies—the acetoacetic acid, β hydroxybutyric acid, and acetone. Theseare strong acids that are responsible for ketoacidosis. Their disposalis an oxygen consuming path way that further saturates fetal oxidativemachinery.

In the fetal hypoglycemic states with proportional hypoinsulinemia, thefat depots are mobilized by the unopposed hormonal lypolytic effects.With the resultant acetyl-CoA in enormous amounts, and fat utilizationvia beta oxidation, not only 33% of excess oxygen is used, but also moreis required to dispose of ketone bodies, and alleviate acidosis. Thereis sufficient evidence in the literature to indicate that in the healthyfetus of normoglycemic status, all the lipid components crossing theplacenta will be used for anabolic purposes and invariable bodilyfunctions, and rarely for catabolic purposes.

The Protein Metabolism

PROTEINS are complex and generally high molecular weight organiccompounds made of AMINO ACIDS that are distinguished by the presence ofan amine group (—NH₂) containing a nitrogenous base, a carboxylic acidgroup (—COOH), and an aliphatic or aromatic side chain of variablestructure specific to each of the amino acid.

The Aliphatic group in a protein signifies an open straight chain,whereas an aromatic group is a closed benzene-like ring structure, as inproline, tyrosine, histidine, phenylalanine, and tryptophan. The socalled nutritionally essential amino acids (10 in number) must be onlyderived from the diet, and the rest, the non-essential amino acids (12in number), by virtue of their short biosynthetic pathways, can besynthesized within the body. Despite the nomenclature, all twenty two ofthe ‘proteinogenic’ amino acids are essential for optimal health, in allstages through life. Though glucose is considered as universal fetalfuel, there is uncompromised need for all amino acids throughout theintrauterine life—not only as the structural elements of the muscle bulkof the developing fetus, but also as the integral micro-components thatrange from enzymes/hormones/neurotransmitters to nucleic acids that makeup the essential architecture of DNA and RNA.

Proteins/amino acids, unlike D-glucose, are extravagant members in termsof expending oxygen or ATP throughout their metabolic processes,including processes involved in disposal of some of their end products.Indeed their oxygen or ATP requirements are even more than their abovediscussed lipid counterparts, and their use as energy source as in IUGRis undoubtedly coupled with enormous ATP/oxygen wastage, though it maynot be the case in an optimally growing fetus. Proteins are the uniquemembers that generate major excretory products—the ammonia, uric acid,CO₂, and the creatinine, that all need immediate and ongoing disposal,whereas CO₂ is the only excretory product culminating from thebreak-down of the carbohydrates and of the fats. For the disposal of thetoxic by-product of protein break down i.e. the ammonia (NH₃ ⁺, derivedfrom the amino group), significant energy needs to be expended for thesynthesis in the liver, of relatively non-toxic urea, from the ammoniumradical and the CO₂.

The metabolic energy yielding end products of protein break-downcomprise of acetyl-CoA, or else the intermediates of the path ways ofglycolysis-citric acid cycle (ex—pyruvate, oxaloacetate, succinyl-CoA,α-ketoglutarate etc), wherein they merge for their ultimate catabolicdisposal, to produce ATP via the respiratory chain. Similar to betaoxidation of lipids, they also produce some ATP (through the NADH+H⁺)during their catabolic break down before merging into the citric acidcycle, but through the metabolic steps and through the ultimate disposalof their excretory products, there is surprising net loss of ATP for anIUGR fetus (due mostly for the ammonia disposal as urea, in some casestwo or more of ammonia molecules derived from multiple amine-groups ofan amino acid), a situation worse than what was encountered during betaoxidation of lipids, that was already critically viewed by objectivemathematical analysis as far inferior in comparison with the unsurpassedyield via the pathways of glycolysis, in terms of the ATP production vs.O₂ expenditure. The discussion of urea synthesis is essential tounderstand the needs of ATP in this cyclic maneuver of ammoniaexcretion, invariable due to amino acid utilization of what ever nature,within the fetal body.

Urea synthesis—the urea cycle starts with L-Arginine that combines withwater to cleaves off 2 of it's amino groups as urea, while also formingornithine that combines with carbonyl phosphate (that is formed by 1molecule of CO₂ and 1 ammonium ion, in the presence of 2 ATP, the latterforming 2 ADP), to form citrulline. One more molecule of ATP is againconsumed to be liberated as AMP and PP₁ in a reaction wherein citrullineproceeds with also an integral participation of the amino group ofL-aspertate to form fumarate, also regenerating L-arginine in theprocess. Fumarate regenerates L-aspertate to continue the urea cycle inconjunction with the regenerated L-arginine. In this process, anequivalent of 4 high energy phosphates (4 ˜{circle around (P)}) are usedfor the disposal of each molecule of ammonia.

The Metabolic End Products of Amino Acids Enter the Citric Acid Cyclewith ATP Debt; However, they are Vital Fetal Requirements as DiscussedBelow—

The above mentioned ATP debt is similar to oxygen debt the muscle incursafter intense activity. It is intended to express that in an IUGR fetusthe supposedly energy/ATP yielding major food stuff, the ‘protein’ init's catabolic break down and via it's by-products (through ammonia,during it's non-toxic disposal) expends significant amount of oxygen/ATPwith net loss of either or both, before any energy/ATP can be producedlater on, in the citric acid cycle. Net loss is the term herein used todenote ATP spent for other than energy-yielding or anabolic purposes orpathways, or oxygen spent in unusually significant amounts. Such netloss incurred even before the entry of the protein metabolic endproducts into citric acid cycle to generate ATP, as exemplified throughthe maneuvers of some of the amino acids, is summarized below—

-   -   1. Histidine—it is metabolized to α-ketoglutarate (that        ultimately merges citric acid cycle). No ATP is produced via        production of NADH+H⁺ during it's catabolic break down, yet 2        molecules of ammonia are produced in the process that expend 8        ATP to be incorporated into urea. Hence, there is a net loss of        8 ATP. Nevertheless, this essential amino acid, as it's        metabolite N-Formiminoglutamate (Figlu) is vital for it's role        in folate metabolism, and the need of folic acid is invariable        for normal fetal development.    -   2. Tryptophan—this is the only amino acid that utilizes three of        molecular oxygen (3O₂) during it's metabolism, and generates        acetyl-CoA, with no production of ATP in the process. Due to the        presence of 2 amino groups, 8 ATP are lost in urea production.        As each O₂ is equivalent to/produces 6 ATP via respiratory        chain, for a hypoxic fetus there is a theoretical net loss of 26        ATP during it's metabolism. However, tryptophan is an essential        amino acid, and it's metabolite the 3-hydroxy-anthranilic acid        is required for the synthesis of nicotinic acid (the niacin) and        of the nicotinamide, the source in the body for NAD⁺, the        universal coenzyme required in all metabolic path ways, in all        cells. Ironically, the most needed of amino acid is also the        most expensive to the fetus. However, nature has devised that        the ubiquitous co-enzyme NAD⁺ to be completely recyclable during        it's most vital function of oxidative phosphorylation.    -   3. Arginine—it is an amino acid containing more than two amino        groups. Two are disposed of as urea, exceptionally without use        of energy, yet the other two will need 8 ATP to be expended for        their ultimate disposal as urea. During it's catabolic break        down into α-ketoglutarate, 3 ATP are produced with ½O₂ through        NADH+H. There is net loss of 8 ATP. However, the role of        arginine is significant—as insulin secretogogue; in urea        synthesis; and in the production of nitric oxide (responsible        for fetoplacental vasorelaxation, trophoblastic invasion, and        for placental vasculogenesis) whose half-life is only 3-4        seconds, and needs to be continuously produced in the body for        it's specified vital functions during pregnancy or otherwise.    -   4. With threonine, there is net loss of 5 ATP. With methionine        there is a net loss of 6 ATP, however, it is vital that it        generates choline, needed for the synthesis of acetylcholine,        lecithin and sphingomyelin. Lysine, aspergine, Glutamine—with 2        amino groups, there is 8 ATP loss.

Rest of the amino acids have to invariably expend at least 4 high energyphosphates in a similar manner consequent to their catabolic break down,outside the citric acid cycle (unless the NH₄ ⁺ is used for synthesis ofnon-essential amino acids in an IUGR fetus) and no amino acid escapessuch fate (except arginine, disposing off two amino groups initially,without expending ATP, as above specified), though some form differentintermediate amino acids that have to yet ultimately undergo deaminationto form ammonia, and then urea, by using 4 high energy phosphates.

In an optimally growing fetus the ammonium ion (NH₄ ⁺) and the glutamine(derived from ammonia in tissues) are used for the synthesis ofnon-essential amino acids, thus maintaining positive nitrogen balance(unlike an adult whose nitrogen intake matches nitrogen excretion)essential for growth. In IUGR, the fetal body protein is used for direenergy needs with net gain of only few ATP. The normal AF urea contentis 2.8 mmol/L at 16 weeks and 3.8 mmol/L at 34-36 weeks with increase toterm, which is 3 times lower in concentration than it's content in thefetal urine itself. The non-essential amino acids are in turnsynthesized from other amino acids/carbohydrate intermediates, and hencecan be a suboptimal process in the IUGR fetus that is obviously forcedto the verge of negative nitrogen balance. The energy expending ureasynthesis may also be impaired in IUGR with consequent oliguria, as ureais a powerful osmotic diuretic, and it is questionable if an IUGR fetuscan maintain an optimal blood ammonialevel. Such a need of ATP requiringwaste disposal is not encountered in glucose/fatty acid cataboliccombustion.

The Standard Food Energy Comparisons—

Conventional standardization of food energy for the sake of comparingnutritive values of foods take into account only the kcal of energy theyproduce per unit mass. The carbohydrates and proteins are considered toproduce the same amount of energy, and the fats double that energy. Ithas to be noted that these comparisons are made in terms of unit mass.Carbohydrates available in nature are packed with substantial watercontent per unit mass, their H⁺ and O₂ content configured in the sameratio as that of water molecule (as 2:1). On the contrary, the fats aredesiccated during their biosynthesis from the parent carbohydrates(review biosynthesis of palmitic acid wherein during steps 5 and 7, awater molecule is lost). Accordingly, one may not be misguided by suchcomparisons (meant for adults/ex-utero food energy standards) whileappraising the fetal energy economics, for the following reasons—

1. The economics of oxygen is highly critical—The value of differentclasses of fetal fuels has to be determined with great discretion, dueto the fact that it has to be measured in terms of calories of energy orATP generated per unit amount of oxygen expended as the economics ofoxygen is strictly accountable due to the relative hypoxia that thefetus has to survive in-utero. Ex-utero, the expenditure of oxygen isnot critical, with the unrestricted supply of oxygen inherent to suchmilieu, except in disease states where there is supply-demand mismatchof oxygen.2. The STANDARD food energy comparison also does not take into accountthe ATP expended (vs. ATP generated) by any food group—In other words,the net ATP available for energy expenditure after the metabolicconsequences of any food resource is disregarded.

Accordingly, the adult standards of food energy comparisons areirrelevant to apply to fetal nutrition and growth, and proteins that areotherwise considered as equivalent to carbohydrates, and fats consideredas superior yielding double in terms of the energy/nutritive value,indeed drastically fall short of such exalted expectations while thefetal energy requirements in the uterine habitat are criticallyappraised, as is befitting to such eco-system.

The IUGR Diet with Vitamins and Other Essential Nutrients—

It can be stated that the passage of all the essential nutrients throughthe placenta are impaired in placental insufficiency. Thiamine and theother B-complex factors would not be an exception, and they are bettersupplied through maternal supplements rather than transamniotic. Suchdeficits can be primarily due to placental impedance, and secondarilydue to hypoglycemia and impaired D-glucose derived-ATP mediated activetransport, necessary for their passage into the fetal compartment, aswill be extensively discussed in later sections. Thiamine is essentialfor carbohydrate metabolism in it's catabolic role of the conversion ofpyruvate to acetyl-CoA, by pyruvate dehydrogenase complex, as wasadequately discussed. If the fetus is deficient in it, substantiallyincreasing glucose loads can be over-whelming to the fetus, and cancause accumulation of pyruvate that can cause pyruvic acidosis andlactic acidosis, and all the path ways where glucose and pyruvate areneeded come to a halt. Additionally, pyruvic acidosis in the mother dueto pre-existing thiamine deficiency exaggerated after glucose load, withit's beri-beri like symptoms can cause acute/chronic maternal heartfailure. Accordingly, planned supplementation of thiamine (initially as100 mg IM/IV before any glucose supplements, and oral tabletssubsequently) is essential to all patients, as malnutritional state forwhatever reason (vomiting, alcoholism, food pica, or a suboptimalnutrition/use of prenatal care in developing countries) can be common,and is under-diagnosed in this subset of population. 100 mg of thiaminesupplements would increase the levels of thiamine presented at theintervillous space thus ensuring adequate amounts reaching fetalcirculation (by achieved Vmax of the substrate transfer mediated by thecell membrane transporters/carriers, as discussed earlier, and this isapplicable to all the supplements). Only small amounts of thiamine arestored in the body (25-30 mg), and it's daily need increases as thecarbohydrate intake increases. In the adults, unlike other vitamins,daily/short term thiamine requirements are calculated based onconcomitant carbohydrate intake. The hypothesis of relative thiaminedeficiency in the fetus in the face of impeding glucose load may not bepractically found in all growth restricted fetuses, but as there is noeasy way of knowing, additional supplements at least would not harm.

Niacin or nicotinic acid, from which NAD and NADP are synthesized, andriboflavin from which FAD is produced in the body, are also essentialfor optimal carbohydrate metabolism. So also, the folic acid and thephosphate supplements (see the role of phosphate in the section of‘oxidative phosphorylation’) are essential. It was discussed under thesection of protein metabolism, how the fetus has to expend significantnumber of ATP during the catabolic break down of one molecule oftryptophan, if 1 NAD/NADP were to be synthesized from this amino acid inthe fetal body, and many such have to be synthesized, as the requirementof this coenzyme is a mandate to every cell, metabolizing orreplicating.

For patients with fetal IUGR on IV D-glucose supplements, with orwithout also of transamniotic supplements, it is therapeutic to advise adiet mostly of carbohydrates, both simple and complex, for the immediateand for the sustained release of hexose sugars, and the proteins andfats as per pregnancy requirements, but rich in essential amino acids,essential fatty acids, vitamins, and of minerals—called the IUGR diet.The idea is based on the advantage of mostly carbohydrate utilization bythe fetus, and likely fat anabolism in the fetal body (a process veryessential for developing brain), and of no fat or protein catabolism forenergy requirements through excesses of extrinsic supplies (FFA and theamino acids coming across the placenta are best laid down to make up thebody bulk of the fetus). The above, by no means imply that the so callednon-essential amino acids or non-essential fatty acids are not essentialto the fetal growth and maturity. Maternal supply of these are equallyimportant, as per the normal pregnancy requirements, as even the normalfetus may not adequately biosynthesize them. Snacks similar to IUGR dietare advisable between meals and during mid-night. Due to pregnancy pica,and the specific dietary requirements, it is imperative that thesepatients have a consult with a dietician, and also with a diabeticendocrinologist until they are stabilized.

Along with the diet that usually contains complex carbohydrates, to alsoensure intake of simple, rapidly absorbable hexose sugars (as specifiedin the above IUGR diet), 25 grams of D-glucose powder in water, taken bymouth few minutes before each meal and breakfast, and along with eachsnack, should be a mandate, incorporated into the maternal dietaryprotocol for the treatment of fetal IUGR both at home, and in thehospital. At least 1 egg with each meal including breakfast is stronglyadvised, as this simple and the least expensive diet is a referenceprotein against which all proteins are measured for their quality andfor the completeness of essential and of highly useful amino acids.Based on moderate prevalence of vegetarians by ethnicity/religion orhabit, it can be easily accepted by any patient-type. Marine Fish canalso be included in the diet. Fish oils were proved to increase birthweight in a study of natural birth weight in Faroe islands (compared tothat in Denmark, popular for it's beef industry) where fish is thestaple diet (Olsen et al, 1986). The principal marine fish oil is ω3eicosa-pentanoic acid that competes with the arachidonic acid as asubstrate for the cyclooxygenase enzyme, to produce prostacycline ratherthan thromboxane A₂ (T×A₂) (Leaf A et al, 1988). Prostacyclin is thenature's potent vasodilator, with probable action at the placentallevel.

The Accompanying Problems Of Placental Insufficiency—their Causes,Normal Fetal/Pregnancy Adaptation, and Possible Relief by InducedFetal/Placental Normoglycemia by Transvenous or Transamniotic D-GlucoseSupplements Along with the IUGR Diet

It is a legitimate concern that the isolated treatment of impairedplacental glucose transfer by therapeutically induced transient episodichyperglycemic state in the mother can not correct the other problems offeto-maternal exchange, inherent to the placental insufficiency, and allthese problems not modifiable and operating together would be stilldetrimental to the fetal well-being. It is also a critical concern thatadequate glucose availability in hypoxic conditions can lead toanaerobiosis and lactic acidosis. The seemingly legitimate concerns asthe foregoing, in the face of therapeutically induced normoglycemicstatus of the fetus, need in depth biochemical exploration. It is theultimate aim of this writing to detail the intricacies and prove, alsoby valid scientific data, that the maternal hypertonic D-glucosesupplements can indeed correct the other problems of placentalinsufficiency also to a moderate extent, so that a healthy fetus withacceptable in-utero weight gain can be anticipated. There are few notwell known yet superb benefits of restoring the optimal glycemic statusat the fetoplacental level that are also enumerated under this section,along with the discussion of the much feared and notorious metabolicproblems of placental insufficiency that were well documented in themedical literature, but so far not clinically or theoretically (acritically and a rationally woven thought can be the forerunner of anequally rational clinical solution) alleviated to the satisfaction of acritical or an inquiring reader. They are listed, and later discussed inthat order, in the following sections.

1. Improved fetal hypoxia (a demand/supply mismatch of oxygen at tissuelevel, having immediate or delayed adverse consequences).2. Improved fetal hypercapnea (above normal blood CO₂ that can haveadverse effects).3. Improved fetal oliguria (suboptimal urine production)/oligohydromnios(suboptimal amniotic fluid volume, corresponding to the gestationalage)—with or without low fetal urea production.4. Improved fetal acidosis (excess hydrogen ion concentration in theblood lowering blood pH), including ketoacidosis.5. Improved fetal hyperlacticemia (excess of blood lactate, withimpeding lactic acidosis, mainly due to anaerobic glycolysis) and lacticacidosis, or else pyruvic acidosis that need a special and separatemention apart from acidosis specified under 4 above, as unlike fetalacidosis in general, the improvement of fetal lactic acidosis isconsequent to improved fetal hypoxia, or consequent to improved fetalthiamine (and other B-complex factors) levels.6. Improved fetal hypertriglyceridemia.7. Improved fetal acquisition of major nutrients like amino acids andfats, and also of minerals, vitamins, and trace elements.8. Effect of D-glucose on: (a) improved placental L-arginine uptake—forthe synthesis of nitric oxide, and for the restoration of fetoplacentalvasculogenesis and vasorelaxation; (b) improved placental D-lysineuptake—for it's possible role in placental vasculogenesis—both in turnimproving hypoxia and the maternal-placental exchange.9. D-glucose mediated growth and maturation of vital organs like fetalbrain.10. Improved ATP production (via operating citric acid cycle, secondaryto restored fetal normoglycemic status), the ultimate key as theubiquitous need for all life forms, and for all life sustainingsubcellular activities.

The enlisted and discussed accompanying problems of placentalinsufficiency are either naturally improved by normal fetal/pregnancyadaptations, or else positively altered by the therapeutically inducedmaternal hyperglycemia or by the transamniotic isotonic D-glucosesupplements, and the consequent fetal normoglycemia.

1. The Improvement of Fetal Hypoxia

Impaired oxygen diffusion across placenta is a deleterious consequenceof placental insufficiency. In the fetus there are many adaptive devicesinherently developed, or else manifested in an exaggerated manner due toplacental insufficiency, as is described below. If that fails, thetherapeutically induced fetal normoglycemic status can surprisinglyalleviate such problem.

-   -   1. The fetus has high cardiac out put, proportional to the        normally high fetal heart rate (an average of 140/minute)        showing beat to beat variation in relation to oxygen demand. The        minute volume, as a multiplied product of stroke volume and of        the heart rate is widely variable, responding to transient or        relatively prolonged hypoxic insults in-utero.    -   2. The fetus has high RBC (red blood corpuscles) count, and the        RBC also has high MCHC (the mean corpuscular hemoglobin        concentration), both substantially increasing the fetal blood        oxygen carrying capacity per unit volume, and unit time.    -   3. The Bohr effect, and the Haldane effect—Secondary to maternal        hyperventilation induced by progesterone, there is lowered PCO₂        in the maternal placental sinusoids. The low PCO₂ of the        sinusoids to start with (a) causes net higher diffusion of CO₂        (with a diffusion coefficient 20 times that of O₂) from fetal        blood, thus reducing the PCO₂ of the fetal blood proportionally,        and (b) the fetal blood becoming more alkaline as a result of        (a). The effects of (a) and (b) in the fetal blood shift the        oxygen dissociation/association curve to the left of higher        oxygen association, due to the Bohr effect that says—the oxygen        affinity towards hemoglobin is inversely proportional to both        the H⁺ ion concentration and the PCO₂. The above two changes of        Bohr effect in the fetus are augmented by (c) fetal hemoglobin        having low affinity to 2,3-DPG (2,3-diphosphoglycerate) (the        2,3-DPG causes the stability of deoxyhemoglobin)—a property        responsible for the greater affinity of oxygen to fetal        hemoglobin (see also subsection-6 of this discussion containing        further elaboration).

In the maternal blood, uptake of CO₂ and fixed acids (like lactic acid)decreases the oxygen affinity for hemoglobin with further release ofoxygen (the double Bohr effect), whereas in the fetal blood, binding ofO₂ with hemoglobin releases more of CO₂ from the blood by the Haldaneeffect, thus increasing oxygen carrying capacity of fetal hemoglobin.The Haldane effect says that the binding of O₂ with hemoglobin releasesmore of CO₂ from the blood. The Haldane effect is also heightened byglucose/ATP mediated arginine active transport, nitric oxide synthesis,placental sinusoidal dilatation, and improved placenta oxygenation,leading to increased oxygen uptake by fetal RBC (in this writing,glucose and ATP are at times referred as if analogous—it is for thereason that glucose is critically acclaimed for it's highest ATP yield,and additionally, it is the therapeutic modality of this invention,further augmenting it's yield).

-   -   4. Normoglycemia can compensate for relative fetal hypoxia, that        is, glucose can compensate for oxygen lack—Utilization of fats        for energy requirements as in β-oxidation not only in starvation        but also in conditions of normal feeding—accounts for about        ⅓^(rd) excess of oxygen consumed (33% more) in the process, as        was shown in the previous sections. The respiratory quotient        (RQ) of fetal tissues in vitro was found to be above 1,        indicating that the fatty acid synthesis from parent D-glucose        molecule outweighs oxidation of fatty acids, which further        proves that the D-glucose is the predominant fetal fuel. With        adequate D-glucose supplements, exclusive D-glucose utilization        compensates for oxygen lack in the IUGR fetus, as it—(1)        precludes beta oxidation of fetal fat depots, saving substantial        amounts of oxygen (33% or ⅓^(rd) of the requirements), (2)        prevents fetal body muscle protein break down for energy        purposes, a process catastrophic in it's oxygen/ATP wastage        compared to glucose, and also worse than oxidation of free fatty        acids, (3) it may be acknowledged at this time that 400% of        absolute oxygen salvage is also achieved via 2-citrate diversion        into rapid fetal lipogenesis in a well-fed state, the further        details of which will be noted in section-9 of this subject.    -   5. The D-glucose improving placental sinusoidal flow/oxygen        delivery—The placenta structurally resembling an arterio-venous        shunt decreases the maternal peripheral vascular resistance,        which in turn increases maternal stroke volume, thus increasing        the filling of the placental sinusoids. The vasculature of the        systemic arterial tree normally ramifies like the branching of        the tree, until it forms the terminal capillaries at the tissue        level. On the contrary, during pregnancy, the uterine vascular        tributaries, the spiral arteries, after entering placenta        progressively dilate, until they form placental sinusoids with        pooling of maternal blood, in which the fetal capillaries are        bathed—a structural arrangement opposite to the terminal        arterial branching elsewhere (visually, the terminal systemic        vasculature resembles the bare ‘winter trees’ devoid of leaves,        whereas the spiral vessels of the placental bed ending in pools        of sinusoids resemble the ‘trees of spring’, their trunks        spreading into bunches of leaves and flowers). Maternal peak        cardiac output, which is found to be 48% higher than        non-pregnant levels is maintained through the gestational period        of 28-30 weeks, but subsequently falls through the rest of        pregnancy to term, which is still 16% higher than the        non-pregnant controls. The coincident increase in the maternal        peripheral vascular resistance from 30 weeks was proposed to be        due to syncytial clumping and proliferation of villi, starting        at this time (Burchell, 1967). However, syncytial changes can        have such direct effects on fetal circulation, but not on        sinusoidal blood flow, that is mainly reflective of maternal        circulatory changes.

It is tempting to think that the growing uterus rising from the pelvismay play a significant role in increasing the maternal peripheralvascular resistance, and the falling of cardiac out-put around 28-30weeks of pregnancy. The aorta bifurcates at the level of fourth lumbarvertebra (L₄), and the inferior vena cava commences at the level offifth lumbar vertebra (L₅). The growing uterus can start to exertpressure on these vessels at about 28-30 weeks. Before that period,there has not been any pressure effects on the pelvic common iliacvessels that travel in close association with the lateral pelvic wall,untouched by the gravid uterus, thus causing the lowered peripheralvascular resistance secondary to placental shunt, fully manifest. It isalso of note that the increase in peripheral vascular resistanceparadoxically correlates with fall in maternal total blood volume,starting at the same time. Considering estrogen effect as uniformlyoperating through-out pregnancy, it could be only the onset of themechanical effects of progressively enlarging uterus on the greatvessels that could raise the peripheral vascular resistance from 30weeks onwards, though maintained lower than non-pregnant levels. Theforward curvature of the spine is maximum at the lumbo-sacral junction(the convexity of the sacral promontory) that can be exaggerated bymaternal lordosis, generally assumed during this stage of pregnancy,both causing pressure effects (as the uterus can not rest wholly ontothe abdominal wall in erect posture, as the anterior pelvic inlet canrestrict such total postural dependency on the anterior soft structures,and in lying down position, the pressure effects on the great vesselsare inevitable).

The placental pooling by the combined effects of increased maternalstroke volume, and due to the decreased peripheral vascular resistanceis also important for the reason that fetal heart rate is twice that ofthe maternal heart rate, and the placental sinusoidal oxygen andsubstrate reserves presented through one maternal cardiac cycle mustadequately serve for sufficient oxygen/substrate exchange through two offetal cardiac cycles, as befitting of the fetal hemoglobin avidlybinding sinusoidal oxygen reserves. The predominantly glucosederived-ATP active transport of L-arginine aids in nitric oxidesynthesis that causes sinusoidal/umbilical vessel relaxation withpooling of oxygen-rich maternal blood around the terminal villi withrestored flow velocity.

-   -   6. The fetal hemoglobin (Hgb) has higher affinity for oxygen—In        the peripheral tissues, a relative hypoxic state in an adult        causes increased accumulation of 2,3-diphosphoglycerate (the        2,3-DPG), an unique metabolite of glycolysis in the erythrocyte.        The DPG greatly stabilizes the T form or the deoxygenated form        of the hemoglobin (Hgb), rather than the R form or the        oxygenated form of Hgb. The 2,3-DPG binds more weakly to the        fetal Hgb than to the adult Hgb, because the H₂₁ residue of the        gamma chain of fetal Hgb is the amino acid serine rather than        histidine (of adult Hgb), and serine can not contribute to the        stability of 2,3-DPG to be positioned in the central cavity of        Hgb molecule. Hence the 2,3-DPG has no significant effect on the        stabilization of the T or the deoxygenated form of fetal Hgb,        and is responsible for the fetal Hgb having higher affinity for        oxygen. Thus, even during hypoxic states, the fetal Hgb binds        avidly with what ever oxygen that is remaining in the placental        sinusoids. In the adult, the 2,3-diphosphoglycerate increases in        the red cells during hypoxic state of the peripheral tissues        that aids the oxyhemoglobin to unload more of oxygen.

The above discussion of increased affinity of oxygen to fetal hemoglobinthat augments oxygen pick up at the placental level, can also give aroom for concern of how oxygen can possibly override such affinity tofetal hemoglobin to deliver oxygen at the fetal tissue-capillary level.The issue is extensively discussed in the continuation-in-part (CIP)application that follows.

-   -   7. Absolute oxygen salvage of 400% by the Fetal brain—the        therapeutic D-glucose supplements sufficiently aid in the        rapidly accomplished neuronal lipogenesis within the fetal brain        by diversion of 2-citrate molecules (instead of one) derived        from 1 molecule of D-glucose, into lipiogenesis, wherein 400% of        absolute O₂ salvage and 200% of absolute glucose salvage are        accomplished. This is true of any rapid lipogenesis (as also in        the adipose tissue) that dominates in the last trimester as in a        well-fed state of the fetus that is responsible for such O₂        salvage. The details are discussed in section-9 of this subject.    -   8. Amniotic fluid (AF) can be a potential source of fetal oxygen        supply—the section ‘Other important source of fetal oxygen        supply’ discusses how AF can be a potential source of an        additional fetal oxygen supply.

2. The Improvement of Fetal Hypercapnia

Impaired excretion of CO₂, that is, the exchange of CO₂ at the placentalsite is a reasonable concern in placental insufficiency. The fetusnormally has following adaptations for CO₂ disposal, that can beimproved due to therapeutic maternal D-glucose supplements:

-   -   (1) The diffusion coefficient of CO₂ is 20 times higher than        that of O₂, and it's diffusion across the cell membranes of        tissue planes, including the lipid bilayer is instantaneous. The        progesterone induced maternal hyperventilation with fall in        maternal CO₂ further compliments the CO₂ diffusion across the        placental interface. Accordingly, the CO₂ diffusion across the        placenta can be still satisfactory, even when the oxygen        diffusion is moderately impaired.    -   (2) The CO₂ sequestration during fetal lipogenesis—lipogenesis        is significantly improved by restored normoglycemia within the        fetus. CO₂ is required in the initial steps of fatty acid        synthesis involving carboxylation of acetyl-CoA to melonyl CoA.        In the synthesis of palmitate, 7 molecules of CO₂ are used, each        derived from blood bicarbonate pool, all being subsequently        liberated as CO₂, during the fatty acid synthesis. However, this        cyclic engagement of CO₂ in fetal lipogenesis sequestrates        significant amount of CO₂ to the area of fatty acid synthesis,        relieving the placenta a substantial burden of it's disposal.    -   (3) The carbon dioxide disposal by urea synthesis—urea synthesis        by fetus increases as pregnancy advances, and significant amount        of CO₂ is used in the process. One molecule of CO₂ combines with        one molecule of ammonia to form one molecule of urea. The urea        synthesis is an energy consuming pathway that can be impaired        during supply-demand mismatch of ATP and can be relieved by        induced fetal normoglycemia with proportionally improved fetal        ATP synthesis, as is discussed in a later section.    -   (4) Low Carbon dioxide production in fetal IUGR—CO₂ is more of a        by-product of carbohydrate metabolism. It is imperative that 1        molecule of glucose and 6O₂ are expended to

TABLE 2 The summary of CO₂ production within the fetal body Source ofCO₂ needed elements/ production processes the source of the elements 6CO₂ - through 1 molecule of glucose, D-glucose, and O₂ - both aerobicoxidation and 6 of molecular O₂ mainly derived through of 1 molecule ofplacental source. D-glucose Anaerobic no CO₂ produced glycolysis 3 CO₂via pentose 3 molecules of NADP⁺ - primarily derived phosphate pathwayD-glucose, and 3 via fetal lipogenesis in the (the HMP shunt) NADP⁺milieu of fetal normoglycemia: fetal synthesis of 1 molecule of palmiticacid generating 14 NADP⁺. 1 CO₂ via 1 glycine, valine, CO₂ source - byamino acid amino acid tyrosine, catabolic break-down outsidephenylalanine, the citric acid cycle. tryptophane and histidine. (someinvolving synthesis of specialized products) Beta oxidation no CO₂produced 7 CO₂ - via fatty acid synthesis glucose is the source ofsynthesis of in the cytosol, from acetyl-CoA; 4 glucose 1 molecule ofacetyl-CoA molecules and 15 ATP are palmitic acid - needed for thesynthesis of one molecule of palmitic acid. CO₂ from lipids/ oxygen, andoxygen - from placental amino acids: during operative citric acidsource; amino acids and disposal as Krebs cycle (mainly from lipids -via placental transfer, cycle intermediates, D-glucose) or through fetalsynthesis or the precursors from D-glucose. (2-3 CO₂ by eachintermediate)generate 6 molecules of CO₂ via glycolysis-citric acid cycle. 3molecules of CO₂ are also produced through 3 molecules of D-glucoseinter-conversion into pentose sugars via HMPS that needs the enzymaticaction of NADP⁺, only supplied by ongoing lipogenesis (that regeneratesthe required coenzyme NADP⁺) for which optimal D-glucose is alsoessential. Very little of CO₂ is produced in lipid and amino acidcatabolic path ways prior to the entry of their intermediates intocitric acid cycle. Only few amino acids like glycine, valine, tyrosine,phenylalanine, and tryptophan produce a net 1 molecule of CO₂ each intheir catabolic break-down. However, fatty acid synthesis generatessignificant amount of CO₂, for example, synthesis of 1 molecule oftryptophan produce a net 1 molecule of CO₂ each in their catabolicbreak-down.

It is obvious that in IUGR, the CO₂ production is directly proportionalto the food substrates (mainly D-glucose) being available, and beingutilized by the fetus (also with concomitant use of molecular oxygengenerally, as citric acid cycle, the major generator of CO₂ is aerobic),and the placental insufficiency imposes CO₂ burden that is onlyproportional to that of associated hypoglycemia and of hypoxia, and nomore (except during oligohydromnios), this stated without giving dueregard for 20 times more efficient disposal of CO₂ via placental route.

-   -   (5) Carbon dioxide needed for the body's base reserve—CO₂ is        also essential for the needed bicarbonate (HCO₃ ⁻) reserve in        the fetal body. Obviously, CO₂ should not be viewed as merely a        product of excretion. This is not to overlook the fact that the        acid base balance is ultimately based on the ratio of carbonic        acid and bicarbonate, to be maintained as 1:20. Both being        produced by CO₂, any further comments in this context can be        only viewed as too simplistic, without needed elaboration.    -   (6) Naturally improved Haldane effect in the fetus, further        augmented by glucose supplements—fetal hemoglobin with more        affinity for O₂, avidly binds with it in the placental        sinusoids, even at low PO₂. As per Haldane effect, binding of O₂        with hemoglobin causes more of CO₂ release from the (fetal)        blood. Glucose-ATP driven active transport, placental arginine        uptake, nitric oxide synthesis, and consequent placental        sinusoidal dilatation—can further result in improved O₂ transfer        to the fetal hemoglobin, in turn releasing more of CO₂ from the        fetal blood.

Additional source of fetal carbon dioxide content—The fetus also hasadditional CO₂ source—the amniotic fluid. Amniotic fluid hassignificantly high CO₂ content. Because of it's high diffusioncoefficient through any tissue types, CO₂ diffuses easily into theamniotic fluid from the highly vascular and metabolically activemyometrium (with exponentially increased cellular mitochondria, and veryactive citric acid cycle that generates significant amounts of CO₂)around the whole of amnion, all through pregnancy. The fetus swallowingamniotic fluid also swallows significant amounts of CO₂. It is obviousthat through the portal circulation CO₂ enters the fetal liver, where itis utilized for urea synthesis to dispose of ammonia from fetal blood.Fetal blood so depleted of excess CO₂ and also of toxic ammonia, entersthe inferior vena cava and then the right atrium, where from the bloodis preferentially diverted to the left atrium to enter the proximalaorta, the supplier of more oxygenated and detoxified blood to the fetalvital organs (the heart and the brain).

The above discussion makes it clear that CO₂ plays vital role in thefetal body, and the prevalence of hypercapnia is not to be unduly fearedfor the reason that the CO₂ production in the fetal body is actuallyproportional to both oxygen and carbohydrate utilization, and moreimportantly the CO₂ diffusion across the placenta is deemed to beefficient. It can be further stressed that glucose/oxygen deprived IUGRfetus will have proportionally decreased CO₂ production.

However, there are clinical situations in which the so far discussedbiochemical norm can be off-set. The very high diffusion coefficient ofCO₂ that serves the fetus well at the placental site, can also be it'sundoing, that in the case of oligohydromnios the amniotic cavity can behighly saturated with CO₂, which the fetus swallows falling into avicious cycle of hypercarbia (hypercapnia) and acidosis. The CO₂ canalso diffuse into the fetal blood through the umbilical cord. Thesequential elaboration of such fetal acidosis is done in the followingsection-3.

3. The Improvement of Fetal Oliguria/Oligohydromnios/Fetal Acidemia(with or without Low Urea Production)—

There are instances in literature where placental insufficiency wasmentioned to be associated with exponential hypercapnia and acidemia(Nicolaides et al 1989). This seems untenable as CO₂ production isdeemed to be low in IUGR (for the reasons explained above), as the fetusis also deprived of oxygen/D-glucose, the sources of CO₂ via the citricacid cycle. There must be an independent mechanism responsible, becausethe source of CO₂ production/hypercapnia is evidently not the D-GLUCOSEin an IUGR fetus, but paradoxically, it is the lack of ongoing D-glucosemetabolism materialized as the citric acid cycle, the virtual source ofATP (it can be noted that 4 ˜{circle around (P)} are needed for thesynthesis of 1 molecule of urea, as shown in the below simplifiedequation). In this setting, the possible causes of such findings can becomplex, and can be explained as below—

The AF normally is high in CO₂, which an IUGR fetus continues toswallow, but there can be impaired disposal of CO₂ in the fetal liver.Ammonia normally combines with CO₂ in the fetal liver cells to formurea, both being so removed from portal circulation. Synthesis of 1molecule of urea expends 4 high energy phosphates which meanssignificant energy is expended in making this product of excretion (seealso the discussion of urea synthesis in the earlier section of ‘Proteinmetabolism’). Deficiency of ATP from citric acid cycle due tohypoglycemia or hypoxia, can be responsible for less or no ureaformation, leading to fetal oliguria, as urea is a powerful osmoticdiuretic. A simplified reaction of urea synthesis is schematically shownbelow, wherein the 3 ATP resulting in 2 ADP and 1 AMP, instead of 3 ADP,will amount to expending 4 ˜{circle around (P)}—

1. Low or no urea production in the fetal liver and the fetal oliguriacan lead to oligohydromnios. However, due to high diffusion coefficientof CO₂ (a property that makes it naturally attracted to water molecule),the diffusion of CO₂ from the myometrium (that is metabolically veryactive through pregnancy, generating CO₂ via citric acid cycle) into theamniotic cavity will continue, and it's proportion starts to mountsteeply due to lowered amniotic fluid volume. Lowered renal perfusion inIUGR (due to fetal auto-regulation of circulation) can also primarilyand independently contribute to oligohydromnios, and the amniotic cavitycan be virtually a small sac of carbonated water for the fetus toswallow.2. With exceeding CO₂ content in the AF, even for small amount of itswallowed, the fetus will be swallowing fluid highly saturated with CO₂that will be entering into the fetal blood via portal circulation, butnot disposed of as urea due to impaired urea cycle, and will beinvariably reflected in the umbilical artery via it's transit to theplacenta, where it may be disposed off. CO₂ can also diffuse into theumbilical cord from the AF. In the absence of urea production andprogressing oligohydromnios, a vicious cycle of CO₂ accumulation sets upwithin the fetal blood.3. Though the AF is known to contain the amino acids (for the neededL-aspergine, and L-arginine for urea synthesis) in a proportion similarto maternal plasma, still sufficient amounts of D-glucose, and ongoingcitric acid cycle are required for the significant amount of ATP neededfor urea production. It was earlier noted that both the specified aminoacids are also regenerated in the cyclic maneuver of urea synthesis,implying ATP availability as critical and paramount.

It can be summarized that fetal oliguria can be primarily due to renalhypoperfusion, or primarily due to suboptimal urea production, or acombination of both in severe cases. It is obvious that improved fetalD-glucose levels and adequate ATP synthesis deemed to operate in optimalurea production leading to osmotic diuresis, can break the vicious cycleof fetal oliguria/oligohydromnios.

4. The Improvement of Fetal Acidosis—

The causes of acidosis in IUGR—Acidosis is an anticipated concern inacutely or chronically distressed fetuses. It can be more so in thesetting of fetal IUGR—due to the combined effects of (1) lactic acidosissecondary to hypoxia, (2) keto-acidosis secondary to hypoglycemia, and(3) depleted reserves of the bicarbonate base (HCO₃ ⁻) that is generallyreplenished through the citric acid cycle. The depletion of HCO₃ ⁻ basein a similar setting can be clinically seen in diabetic keto-acidosis,wherein despite the prevailing low levels of blood HCO₃ ⁻, by mereinsulin supplements and by the restoration of blood glucose utilizationvia the citric acid cycle, blood HCO₃ ⁻ is replenished, and the acidosiscorrected. In this clinical setting of diabetic ketoacidosis,supplemental HCO₃ ⁻ is rarely needed, except in extreme life threateningconditions of acidosis.

Relief of Acidosis Secondary to Fetal Lipogenesis

In IUGR, restored normoglycemia, and fetal fatty acid synthesis as aresult, not only regenerates oxidized coenzymes NADP⁺ but also useshydrogen ions. 28 hydrogen ions generated through HMPS are used in thesynthesis of one molecule of palmitate from acetyl-CoA, and melonyl-CoA.During the later months of pregnancy, the lipogenesis that takes placein a normoglycemic fetus can dispose off enormous amount of hydrogenions from the fetal body, generated mainly via universally ongoing HMPS.During hypoglycemia there will not be any lipogenesis. On the otherhand, lipolysis and beta oxidation are initiated for energyrequirements, further made more prominent by decreased insulin levelssecondary to hypoglycemia (insulin is anti-lipolytic that normallyantagonizes the many lipolytic hormones in the body—like the growthhormone, the adrenocorticotropic hormone, and the glucagon). But in theabsence of sufficient amounts of D-glucose and lack of oxaloacetate,acetyl-CoA produced via beta oxidation of lipid break-down finds noentry into citric acid cycle, and is fated to produce ketone bodieswhich are moderately strong acids. Once they are formed, even if glucoseis made available, the ketone bodies are oxidized in preference toglucose, thus saturating the oxidative machinery. Normoglycemia cancompensate for relative hypoxia by 33%+400%+10%, by various metabolicconsequences, but obviously oxygen can not compensate for hypoglycemia,and the related metabolic consequences.

Acidosis can also be produced when IUGR is also associated with fetaloliguria/oligohydromnios, a grave clinical concern that can virtuallylead to a moribund fetus. This scenario was described elaborately in theimmediate preceding section-3.

5. The Improvement of Fetal Lactic Acidosis/Pyruvic Acidosis—

This is discussed separately from fetal acidosis in general, as fetallactic acidosis is unique in that, unlike other types of metabolicacidosis, it is only cleared by resolution of hypoxia, it's causativepathology. The D-glucose supplements can correct the inciting pathologyby improving fetal hypoxia by various means, as discussed in the sectionof ‘Improvement of fetal hypoxia’. If not, supplemental oxygen therapycan alleviate acidosis as will be seen in the elaborate discussion in asubsequent section. Thiamine deficiency can also cause lacticacidosis/pyruvic acidosis, and can be relieved by thiamine supplements,advocated as a mandate to the D-glucose supplements.

During hypoxia secondary to placental insufficiency, the fetus canresort to anaerobic glycolysis that generates significant amounts oflactate, but production of only 2 ATP from 1 molecule of D-glucose. Dueto lack of pyruvate, the usual end product of glycolysis under aerobicconditions, the citric acid cycle is not made possible. Only therestoration of normoxia (optimal blood/tissue oxygenation that meets thedemands) can relieve lactic acidosis, when pyruvate is regenerated fromlactate via reversal of the step catalyzed by lactate dehydrogenase,and/or by thiamine supplement, if needed, when pyruvate is oxidized toacetyl-CoA by pyruvate dehydrogenase to enter citric acid cycle, greatlyenhancing the reversal of the reaction generating pyruvate from lactate(see also the last SECTION of this specification ‘Neonatal care of anIUGR baby’).

Lactate is an important fetal substrate being constantly supplied to thefetus by the placenta. As glycogen formation is not without significantamount of ATP consumption, the placenta stores glucose less as glycogen,and more as lactate, the predominant placental carbohydrate reserve thatit supplies to the fetus throughout gestation, the best example ofnature's efficiency and wisdom of what looks like nature's folly. Theglycogen synthesis expends 2 ATP for each glucose molecule to beincorporated, whereas lactate production generates anaerobically 2 ATPwith a total potential gain of 4 ATP in it's making, compared to thealternate means of placenta storing glucose as glycogen. The fetalbrain, heart, and skeletal muscle can convert lactate into pyruvate, viathe lactate dehydrogenase reaction, when NAD⁺ is converted to NADH+H⁺ togenerate 3 ATP aerobically, while the ATP yield to the fetoplacentalunit is similar to that of aerobic glycolysis. The lactic acidemiabecomes a metabolic concern only after prolonged anaerobic glycolysis ofglucose by the fetus during unrelenting hypoxic conditions as inplacental insufficiency, whereas normally lactate is the fetal fuel justlike D-glucose, only efficiently saved. Nonetheless, it can not beconcluded without saying that ‘no two metabolic products cause moreapprehension to the explorers of fetal medicine than the lactate/lacticacid and the CO₂, as it is hard to fathom when they may turn against, assimilar to man's tools, the swords and the guns, they also both save andkill!

Persistent fetal lactic acidosis can be reflected in the AF (amnioticfluid), as kidney is an effective organ both in metabolizing andexcreting the lactic acid, and the fetal urine passed into AF canreflect the fetal lactic acid levels. Fetal kidney also excretesprogressively increasing amounts of creatinine as the organ matures init's function. Thus AF creatinine content is a reflection of fetalmaturity.

The placenta metabolizes significant amounts of glucose anaerobically,and the lactate can diffuse into the AF, the maternal circulation, orinto fetal circulation, but mostly it will be supplied to the fetus. Thematernal venous blood lactic acid/pyruvic acid ratio is 10, whereas itis 12 in the fetus. When the maternal food consumption itself is low, asduring the stretch of time between dinner and breakfast, the placentasupplies it's reserves of lactate to meet the fetal needs. The placentametabolizes 80% of glucose extracted from maternal blood anaerobically,to convert it into/store it as lactate (L. Myatt). In fact, theplacental uptake of glucose is more (50-60%) than the fetus during earlymonths of pregnancy, and it declines only towards term when theplacental pentose phosphate pathway (the HMP shunt, predominantlyrequired for placental elaboration) and other previously dominantanabolic pathways gradually diminish (L. Myatt). Lactate utilizationaccounts for 25% of oxygen consumption in a normal fetus, and contraryto expectations, high fetal lactate levels will not account for/resultin fetal acidosis (J. A. Low). High rate of placental permeability tolactate was observed in hemochorial placentae, as the human placenta.During IUGR with associated hypoxia, the fetus becomes the sole producerof lactate/lactic acid, and the placenta becomes an important site toclear the excess fetal lactic acid, and ceases to be the lactateproducer/supplier, as there appears to be an impaired H⁺/lactateco-transport in the basal membrane of the syncytiotrophoblast in term orpre-term IUGR pregnancies, compared to the appropriately grown controls(P. Settle et al). It seems reasonable to contemplate that the intrinsicglucose needs of the placenta itself having not been met in the settingof IUGR, the placenta loses it's reserves of stored lactate, so that itcan not supply the usual provisions of lactate to the fetus.

6. The Fetal Hypertriglyceridemia

Econamides and associates (1990) who measured fetal triglyceride (TGD)levels demonstrated fetal hypertriglyceridemia that correlated with thedegree of fetal hypoxemia. Barker and colleagues (1993) at the UnitedKingdom's medical research unit had over 20 years researched the causesof adult mortality and morbidity in relation to possible adverseintrauterine life, and found increased risks of hypertension andatherosclerosis in the context of IUGR.

In this writing, the author attributes the adult hypertension andatherosclerosis of above studies to the mode of hypertriglyceridemiaproduced in the IUGR fetuses (as discussed below) that could bepersistent for significant part of intrauterine life. Experimentalresults in animal and in human atherosclerosis studies suggest that thefatty streak represents intimal lesions resulting from focalaccumulation of lipoprotein in the vascular intima. Recruitment ofleucocytes to the nascent fatty streak and their adhesion to vascularintima are further made easier due to sluggish laminar flow because ofpolycythemia and of hyperviscosity of blood in the IUGR fetus. In thisset up at least some amount of thrombotic reaction in the focalatheromatous area is possible. As per the ‘Virchow's Triad’, thethrombosis of a vessel wall depends on three factors—the velocity of theblood flow, the viscosity of the blood, and the nature (injury, if any)of the vessel wall, all being present in the IUGR fetuses in an adversemanner. Accordingly, a ground work is already laid out in-utero, as athromboatheromatous plaque in the vessel wall, as an operation ofVirchow's triad in the set up of persistent hypertriglyceridemia ofintra uterine life that can likely progress and manifest asatherosclerosis and hypertension in adult life. Even a small lesion inintrauterine life can be magnified as the baby grows, and in adult lifeit can assume significant proportion, similar to a mole or a scar on achild's body becoming proportionally bigger in the adult life.

The initiation and the perpetuation of fetal hypertriglyceridemia infetal IUGR can be as follows—insulin is a potent positive stimulus forlipogenesis, and a negative stimulus for lipolysis. It inhibits theactivity of the hormone sensitive lipase (that is different from thelipoprotein lipase) responsible for lipolysis, thereby preventing therelease of not only FFA from the fat stores, but also of glycerol. InIUGR, there is prolonged and persistent hypoglycemia causinghypo-insulinaemia (or hypoinsulinism) resulting in the unopposed actionof other hormones like the GH (growth hormone), glucagon, and the ACTH(the adrenocorticotropic hormone) that causes lipolysis through theirstimulatory effect on the hormone sensitive lipoprotein lipase. However, because of the lack of oxygen needed for beta oxidation of thereleased FFA, they are not used. In this setting, the esterification ofFFA with glycerol in other tissues results, causing fetalhypertriglyceridemia or hypertriacylglycerolemia as is usually seen inadult diabetes.

There can be additional factors operating in the young adult life of theSGA infants who suffered IUGR. Despite hypoglycemia and secondaryhypoinsulinemia (hypoinsulinism) the IUGR babies who survived adverseintrauterine life have been shown to mount adequate insulin responsepostnatally. This is evidenced by the fact that diabetes, if at allmanifests, is only transient in the SGA infants during their neonatallife. However, diabetes can be a problem for them as young adults, asthe growth restricted islet cell mass of pancreas (due to persistenthypoglycemia of intrauterine life) that is hypoplastic (in proportion tothe fetal glycemic status) but not vestigial, may be adequate to cope upwith the blood glycemic demands of early childhood, but not of the youngadulthood, when insulin requirements increase. Moderate hypoinsulinemiaagain becomes manifest, with the consequent lipolysis (insulin beinganti-lipolytic) and hypertriglyceridemia (as described above). Forsignificant number of years it can go unsuspected and undiagnosed, dueto it's uncommon age prevalence, and no associated family history. Thiswill further add to and result in ongoing atherosclerosis andhypertension. The set up is similar to untreated adult diabetesmellitus, with it's associated risks of hypertension, atherosclerosis,and of the early onset coronary artery disease. For such clinicalmanifests, the adult diabetes is categorized as a coronary arterydisease (CAD) risk factor, and the imposed risk considered significantenough to be categorized as equivalent to diagnosed/established CAD.

7. Improvement in Placental/Fetal Acquisition of Major Nutrients (AminoAcids and Lipids), Minerals, Vitamins, and Trace Elements in IUGR—aRelief Expected by the D-Glucose/IUGR Diet Supplements (1) The placentalacquisition of D-glucose

It was adequately described how glucose is transported through cellmembrane by facilitated diffusion in the section ‘The biochemical basisfor hypertonic D-glucose treatment’. In that context it was alsodiscussed how the Michaelis-Menten equation is an expression of therelation of substrate concentration and the resultant rate of anenzyme/hormone or of a cell membrane/cytosol located substrate carriermediated chemical reaction—either by active transport or by facilitateddiffusion. It was discussed with figurative illustration (FIG. 1), howthe maternal hypertonic D-glucose supplements with exceeding substrate(S) concentration can cause exponential improvement in placentalD-glucose transport, by maximal recruitment of substrate carriersimposed by substrate demand, each carrier in turn operating with avelocity approaching Vmax, wherein the Vmax can be instantaneous intime.

Michaelis-Menten equation can also be applicable to the transport of allthe placental substrates (discussed under this section) whoseconcentration can be greatly improved at the placental interface (by theIUGR diet implemented to all the afflicted mothers) such transportfurther enhanced indirectly by induced normoglycemic status improvingATP production that heightens the placental concentration of maternalsubstrates by ‘active-transport’, operative for a great many substancesdirely needed by the fetus, but present in lower concentrations in thematernal compartment.

(2) the Placental Acquisition of Amino Acids

The amino acids are needed for anabolic needs like lay-over of fetalbody muscle mass, and biosynthesis of specialized products such as (a)hormones, (b) enzymes and coenzymes, and (c) neurotransmitters, tomention a few.

It is a saving provision that the AF contains amino acids in the sameproportion as the maternal extracellular fluid, and the fetal swallowingof AF can be a significant means of their acquisition, but not optimal,and hence the contribution of placental transfer is invariable.

Amino acid transport across the microvilli of the trophoblast can beachieved by different means and influences, as follows—

-   -   1. Active transport—it plays a role in the transport of certain        amino acids, prevailing in lower concentrations on the maternal        side, that is, the maternal fetal ratio is less than 1, when        facilitated diffusion is no longer applicable. The process being        ATP dependent, increased glucose availability and ATP production        as a result makes the active transport of amino acids possible.    -   2. Facilitated diffusion—most amino acids are transported to        inside of essentially all cells by facilitate diffusion, a        mechanism involved also in glucose transport, and was already        described. Additionally, insulin, as in glucose transport,        enhances the amino acid transport achieved via facilitated        diffusion. Insulin's effect is neither on glucose nor on the        amino acids, but it is on the regulation/recruitment of the        involved cell-carriers/transporters. The laws of facilitated        diffusion allows placental diffusion of amino acids only down        the concentration gradient, which means that maternal fetal        amino acid ratio has to be more than 1, or else, their placental        passage has to be achieved via energy dependent active        transport, the IUGR diet with exceptional substrate        concentration, especially of essential amino acids obviating        such need.    -   3. Sodium co-transport (symport)—In this mechanism, it is the        concentration gradient of sodium across the cell membrane that        provides energy for the amino acid transport. The involved        carrier has carrier sites both for sodium and for the amino        acids. As the aliphatic or the aromatic side chain of the amino        acids are very diverse in structure, different carrier systems        are operative and specific to different types of amino acids.    -   4. Hormonal regulation—estrogen helps amino acid transport in        the uterus, that is mainly responsible for it's enormous growth        during pregnancy. Similarly, growth hormone influences amino        acid transport through all cells.    -   5. Pyridoxine—Transport of few amino acids are also pyridoxine        (B₆) dependent.

The IUGR fetus, and the effect of IUGR diet—The amino acids may not beadequately acquired by the fetus in the setting of placentalinsufficiency. There is documented evidence in the literature that thecordocentesis of SGA fetuses afflicted with growth restriction in-uteroshowed lower amino acid levels, compared to their appropriately grown(AGA) counterparts, and this especially involved essential amino acidsthat the placenta must transfer. As the levels of placental transporterswere found to be unaffected in the placentae of growth restrictedfetuses, it can be deduced that it is the effect of the failed placentalelaboration, and reduced surface area that influence the amount of aminoacids to be transported. The beneficial clinical manipulation throughIUGR diet is based on the fact that the rate at which the amino acidstransport through a membrane by facilitated diffusion, based also onMichaelis-Menten constant, depends on—

-   -   (a) The concentration gradient of the substance/substrate (S)        that is affected by an exceeding essential amino acid content in        the advocated IUGR diet. Such heightened maternal substrate        concentration can also change energy requiring active transport        to facilitated diffusion.    -   (b) The amount of carriers available—it has no significant        bearing in this setting, as the placental carriers are far from        saturated by the substrate normally, and more carriers can be        recruited in proportion to increased substrate (S) as in (a)        above. Insulin virtually makes the glucose/amino acid carriers        available across the cell membrane.    -   (c) The rapidity with which a physical or chemical reaction        takes place between the carrier and it's substrate—such chemical        interaction is better accomplished during the short span of        fetal systole in IUGR, when the filling of the terminal villi is        more effective than during diastole when there is little end        diastolic filling, or absence of increased end diastolic flow        velocity (as discussed in a later section). As the reaction        velocity is being affected also by substrate concentration (S)        even when other factors are kept constant, there is positive        effect on V_(max), when substrate (S) availability is in        exceeding amount, as provided in the IUGR diet.

The fetal heart rate being 140 per minute, and as the cycle's systolictime is unchanged at any rate, to make such purposeful high rate and abetter systolic villus capillary filling effective, the placentalcarriers must function in a ‘speed mode’ so as to carry enough of neededfetal substrates. Hence, if v₁=Vmax, by a manipulated high substrate (S)concentration, higher will be the substrate transfer. The maternal heartrate being only half that of fetal heart rate, the pools of placentalsinusoidal structure normally compensate with enough of such substratereserve lasting through two of the fetal cardiac cycles.

Restored Transcellular Amino Acid Transport within the Fetal BodySecondary to Normoglycemia and Normalized Insulin Effects—

It is of great significance that glucose supplements and the consequentfetal normoglycemia bestow the double benefit of heightenedtranscellular transport of both glucose and of the amino acids withinthe fetal body, via the normalized hormonal effects of insulin on both.

(3) The Placental Acquisition of Lipids and Free Fatty Acids (FFA)

Only few substances are soluble in water and also in the lipid bilayerof the cell membrane, such few of physiological importance being theoxygen, carbon dioxide, and the FFA. And the primary factor thatdetermines how rapidly a substance can diffuse through the lipid matrixof a cell membrane is the rate of the solubility of the substanceitself. The fatty acids themselves being lipids, solubility barrier inthe lipid bilayer of the cell membrane should be of no concern, and theyare easily diffusible by means of ‘simple diffusion’ across the lipidlayer of cell membrane requiring no carriers, such diffusionproportional to the concentration gradient.

The major factor in determining the transfer of free fatty acids acrossthe placenta is the maternal levels of circulating free fatty acids. Thefunction of Human Placental Lactogen (HPL) is blocking of the peripheraluptake and utilization of glucose by maternal tissues, while alsopromoting the mobilization of free fatty acids (FFA) from the fatdepots, for utilization by the mother. The elevation of serum totallipids, phospholipids, and of FFA during pregnancy is enormous, with aprogressive increase towards term. The total lipids increase by 46%, andthe FFA by 60% during 37-40 weeks of pregnancy. Such high values assurehigh maternal gradient across the placenta for simple diffusion oflipids and the FFA (both the essential and non-essential free fattyacids) into the fetal circulation. The fatty acids so derived contributeto the structural components of the cell membranes, and to the cellulararchitecture of the brain that is predominantly lipid. The risingalbumin levels of the fetus can further help to carry, and mount thelevels of fatty acids. The therapeutic maternal hyperglycemia can alsospare FFA utilization to some extent by the mother.

The increased content of maternal essential fatty acid levels via IUGRdiet will also proportionally increase placental transfer of these fattyacids by the similar principle of simple diffusion. If the FFA levelswere found by the investigators to be much lower in the fetus than themother, it probably is because they are immediately incorporated intothe fetal anabolic processes that further provides needed concentrationgradient, or else the simple diffusion of the FFA would cease. Moreover, the enormous rise of FFA in the mother is purposeful. Themolecular weight of the concerned FFA has a bearing on the kinetics ofdiffusion, the low molecular weight FFA like the palmitic acid diffusingmore rapidly than the high molecular weight FFA like the oleic acid,though the latter is a predominant FFA of the maternal adipose tissue.The palmitic acid is indeed the integral building block of the rapidlydeveloping fetal brain, as will be seen in the later discussion, andhence also is the one most needed from the maternal compartment.

(4) the Placental Acquisition of Minerals, Vitamins, and Trace Elements

Many of circulating fetal elements that are absolutely essential forit's optimal growth, like calcium, iron, magnesium, and iodine are foundto be at higher levels in the fetal side than that of the maternal side,and they are not synthesized by the fetus.

To cite a clinical example, in the case of iron transport, despitesevere anemia clinically manifesting in a mother, her fetus is rarelyanemic. That is why it was appropriately said that the fetus thrives atthe expense of it's mother. Such optimal fetal growth in adversity isachieved by the transcellular, ATP dependent and of a carrier mediatedactive transport, accomplished in the placental tissues directed tominerals, vitamins, and the trace elements that can be normally less inquantity in the maternal blood, yet are absolutely needed more by thefetus.

Active transport—The active transport obeys the same laws of chemicalcombination of the substrate with the carrier molecule, and a specificcarrier molecule (for example—calcium binding protein, or thephosphorous binding protein) is required to transport each type of, oreach class of substance(s) having natural affinity for it's carrier thatmakes the two of them combine readily on the outer surface of the cell,yet on the inside of the cell, energy in the form of ATP is needed fortheir dissociation, this may also needing an enzyme catalysis.

(a) Iron transport—iron is transported through the placental tissue byactive transport. Over all, about 375 mg of iron is needed by the fetusto be deposited as hemoglobin in it's red blood cells. During the firstfew months of pregnancy, the placenta grows rapidly and enormously, yetwhen the fetal growth can be only described as diminutive in comparison.It is for the reason that placenta avidly accumulates proteins, calcium,and iron, to be stored in and used during the later months of pregnancywhen the absorption of some of these elements by the maternalgastrointestinal system is less than optimal. Iron accumulation by theplacenta is more rapid than that of calcium and of the phosphates, andin fact it is concentrated in the progestational endometrium during theluteal phase, even prior to implantation. This iron, ingested by thetrophoblastic syncytial giant cells of the embryo is required for theformation of red blood cells even at this stage. One third of iron atterm is stored in the fetal liver, intended for the use of the neonateduring the early months of life. Placenta functions similar to the fetalliver from early on, in terms of the storage of both carbohydrates andiron, to be liberated and furnished when the fetal demands are more. TheD-Glucose supplements with restored acquisition of glucose by theplacenta and the fetus can enhance the process of active transport ofiron by readily available supply of ATP. It can improve the fetal MCHC.It in turn can regress the fetal polycythemia, and reduce the excessiveproduction of the fetal erythropoietin. Though they are mainly thesecondary effects of fetal hypoxia, yet improved fetal iron and improvedMCHC can have positive bearing in this setting.

(b) Calcium, Magnesium, and Phosphorous Transport—

About 23 grams of calcium and 14 grams of phosphorous are accumulated byan average fetus. Half of this gain is during the last 4 weeks ofpregnancy, when also there is rapid bony ossification, and maximal fetalgrowth. As a saving measure, urinary excretion of calcium falls duringpregnancy, coupled with that of increased intestinal absorption,probably due to estrogen influence. Only extreme maternal deficiency ofcalcium will reflect in the fetus as congenital rickets, which indicatesthat the maternal stores were very deficient, or that the pregnancydefenses failed by some other means. In the case of calcium, there areadditional factors that are also at play in the mother, like theVitamin-D/parathyroid hormone level, just as in the non-pregnant state,and the placental cells are no exception to that influence (see also thecalcium-magnesium antiport below, with regarding placental calciumacquisition). Just as calcium, phosphorous is also physiologicallylinked to the above influences. The foregoing discussions of themetabolic path ways of major food stuffs made very clear of the need ofphosphorous in all anabolic and catabolic processes through it's vitalrole as ATP, generated by the participation of inorganic phosphate(H₂PO₄ ⁻, the dihydrogen phosphate ion) in the life sustaining processof the mitochondrial oxidative phosphorylation.

Magnesium is very essential to the fetus because of it's need in allreactions where ATP/ADP are the substrates. It is transported throughthe cell membrane probably by active transport involving thecalcium-magnesium antiport (an antiport system moves two molecules in anopposite direction) in the same manner as the sodium and potassium ionsare transported involving the sodium-potassium ATPase (in thesodium-potassium antiport, the active transport involves potassium, anintracellular cation coming into the cell, whereas sodium, anextracellular cation getting out, and the system normally transports 3of sodium ions to the outside of the cell, and 2 of potassium ions tothe inside).

Magnesium is mainly an intracellular cation, and calcium anextracellular cation. In the magnesium-calcium antiport, involvingcalcium ATPase, magnesium ions are probably transported into the cell,and calcium ions to the outside. This explains the bidirectionaltransport of calcium in the mammalian placentae. Despite the outwardflux during calcium-magnesium antiport, calcium transfer isindependently controlled and achieved by the facilitation of vitamin-Dand the parathyroid hormone, and also by passive diffusion down anelectrochemical gradient via calcium channels, as maternal calciumlevels are maintained far higher than the non-pregnant levels. Furthermore, fetal net acquisition of calcium is aided by calcium bindingprotein that protects the intracellular calcium from becoming too high,any intracellular excess being not amicable to the normally intendedcellular functions.

(c) Iodine transport—the placenta can actively transport iodide ion bymeans of active transport, as iodide is essential for the synthesis ofthe thyroid hormone from the fetal thyroid gland, and the maternalthyroid hormone crosses the placental barrier only to a limited extent,as obviously, it will impair the development and maturation of fetalthyroid gland by negative feed-back, and the hormone secreted by thefetus deemed to be imposing such feedback.

Fetal acquisition of minerals and trace elements through amniotic fluid(AF)—while all the inorganic substances like the minerals and traceelements can pass through the placenta only by active transport, theycan yet diffuse into the amniotic cavity (in dissolved/suspended statein maternal extracellular water), via the intercellular andintracellular canalicular system all through amnion by means of passivediffusion that needs no energy expenditure. The minerals and traceelements are present in the AF in the amounts proportional to theirconcentrations in the maternal extracellular fluids. The fetus canswallow these elements of the AF, but obviously not in amounts that cancorrect the deficiency imposed by normally needed major placentalconcentration.

(d) Vitamin transport—the vitamins are transported across placenta by‘active transport’ expending ATP, and are found to be in much greaterconcentrations on the fetal side. The ascorbic acid (the vitamin-C)levels on the fetal side are found to be thrice that of the mother.

The mechanism of active transport, and it's relevance to therapeuticglucose supplements—In states of ATP depletion as in IUGR, the transferof the essential minerals and trace elements is invariably diminished,adding to the other major problems of this disease state. Glucose viacitric acid cycle being the major generator of ATP, the therapeuticD-glucose supplements relatively improve the diminutive transport ofthese very essential fetal growth factors, and operating irrespective ofmaternal gradient and in conjunction with the normally surplus provisionof available cell membrane ‘carriers’—it can effectively overrideplacental insufficiency to a moderate extent

The Effect of Insulin on Placental Glucose Transport in Normal and inDiabetic Pregnancy, as Relevant to the Treatment Involved—

With vital control of insulin on the transcellular glucose transport, itis a legitimate question how the babies of mothers with uncontrolleddiabetes are growing to be macrosomic. When insulin controls thetransporters, how glucose is overcoming the placental barrier imposed byinsulin deficiency or resistance in poorly controlled diabetic pregnancy?

Before the advent of insulin, diabetic women conceiving and carrying thebaby to term were rare. This clearly denotes that even the endometrial(decidual) cells need insulin for glucose transport to be stored in theform of glycogen to sustain the growth of the early conceptus. Decadesago, untreated diabetic women also suffered secondary amenorrhea,indicating the influence of insulin and of the required glucose on theproliferation of estrogen-primed endometrium that needs to be shedlater. Accordingly, it is obvious that the diabetic pregnancies becamecommon clinical concern after the insulin therapy became theindispensable tool of the obstetricians.

TABLE 3 The effects of the therapeutic interventions of D-glucosesupplements, and the IUGR diet on the placental transfer of the maternalsubstrates - Element or compound Effect of the D-glucose supplements, orinvolved in placental the IUGR diet on the placental transfer and fetaltransport Mechanism of transport mechanism 1. Simple carbohydratesFacilitated diffusion* Multi-fold increase in placental carrier (by IVD-glucose and controlled by insulin transport by increasing V max, byIUGR diet) secondary to exceeding increase in placental D-glucosesubstrate (S). Complex carbohydrates sustained release of hexose same asabove, to a lesser extent. (by IUGR-diet) sugars from the maternalblood, also by facilitated diffusion 2. Amino acids Facilitateddiffusion through Through maternal hyperglycemia, and cell membranecarriers, through restoration of normal insulin controlled by insulinlevels in the fetal compartment, as an effect of restored fetalnormoglycemia. Through ↑ amino acid substrates (S), as an effect ofmaternal IUGR diet, thus increasing the Vmax, for heightenedtransplacental amino acid transport, via facilitated diffusion. Activetransport † Through generation of ATP, as an effect of restorednormoglycemia in the placenta, and in the fetus. 3. Fatty acids/lipidsSimple diffusion Maternal hyperglycemia sparing some maternal fatutilization, and increasing the placental gradient of FFA. The IUGR dietproportionally increasing the essential fatty acids in the maternalcirculation. 4. Minerals, vitamins, Active transport, some Throughgeneration of ATP in optimal and trace elements. involving ‘antiport’amount as an effect of restored normo- glycemia in the placenta, and inthe fetus. *Facilitated diffusion—specific carrier mediated transport,when maternal fetal substrate ratio is >1; † Active transport—specificcarrier mediated transport needing ATP, when maternal fetal substrateratio is <1.

Maternal diabetes with fetal macrosomia is probably mostly evident intype II obesity associated diabetes in whom central obesity is theculprit, the obese adipocytes in this setting being capable of producingpeptides including cytokines that are capable of modulating the insulinresponse by causing first insulin resistance, and then hyperinsulinemia.The hyperinsulinemia can in turn lead to down-regulation of cellreceptor sites for insulin, on the insulin-sensitive tissues. Thus thetarget tissues over time become markedly insulin-resistant in thesepatients, who in turn need some treatment intervention. Marshall R N etal and Posner B I et al in 1974 demonstrated that the placental bindingprotein of insulin is similar in molecular weight and function to theinsulin receptor protein found on the fat and on the liver cells, thatare also unaffected by a subject's insulin resistance. When diabeticwomen conceive, the placenta just as the fat depots being unaffected bymaternal diabetes, the maternal hyperinsulinemia will proportionatelyincrease glucose transfer across the placental interface, leading tofetal islet cell hypertrophy and then fetal macrosomia.

8. The Effect of Maternal Hypertonic Glucose Supplements on PlacentalL-Arginine and D-Lysine Uptake: The Relief of Hypoxia by ImprovedFetoPlacental Nitric Oxide (NO) Synthesis, and Placental VasculogenesisEffects of Glucose on L-Arginine Up-Take—

Nitric oxide (NO) is a potent vasodilator throughout the body, and it issynthesized from the essential amino acid L-arginine by the action ofNitric oxide synthase. It uses NADPH+H⁺ as a cofactor. Nitric oxide hasa very short half-life of 3-4 seconds, which means it needs to becontinually synthesized. As L-arginine has to be supplied by the mother,increased supplements of essential amino acids via IUGR diet, byimproved substrate (S) concentration and also Vmax, will improve it'splacental intake/transfer so that it can be effective locally—in thespiral vessels, in the villous capillaries, and also in the umbilicalcirculation for generating the needed nitric oxide so as to facilitatetheir vasorelaxation.

The transplacental transport of certain essential and the non-essentialamino acids occurs by active transport as specified earlier, for whichATP is essential. Maternal hypertonic glucose supplements improve theATP synthesis, and thereby the active transport of L-arginine at theplacental interface, apart from also providing the needed NADPH+H⁺generated from the carbohydrate metabolism, involving pentose phosphatepathway (the placenta itself has active pentose phosphate pathway). Asactive transport is also the mechanism by which L-arginine istransported into the endothelial cells of any vessel wall, the glucoseinduced active transport of L-arginine into the umbilical vesselendothelial cells can lead to the synthesis of nitric oxide in thevessel wall that can restore umbilical vessel vasodilatation. Suchimproved impedance both in the placenta and in the fetal vessels shallhave great bearing in incrementing both the flow velocity and of theflow volume in these vessels to over-ride the ‘critical closingpressure’ consequently relieving hypoxia, and also of the accompanyingmultitude of adverse effects involving the placental exchange.

The following researchers from Chile, South America, recently madeinteresting observations of the role of Nitric Oxide in the growth ofthe fetoplacental unit and it's circulation, and also of the effect ofD-glucose in L-arginine transport through cell membrane—

Krause et al (2011) in their placental study proved that nitric oxide isessential in placental trophoblastic invasion, cellular respiration, andalso in maintaining the vascular tone. They further proved that it alsorepresents the main vasodilator function of the placental vessels, andthat it participates in placental vasculogenesis through theangiopoietin signaling molecules. Hence it's role is important even inalleviating prevailing placental pathology.

Sobrevia et al (2009) observed that D-glucose and insulin increasedL-Arginine transport and cGMP accumulation in the Human Umbilical VesselEndothelial cells (HUVEC). It is plausible as noted by the observationsof these researchers that glucose enhanced (and insulin mediated) activetransport is involved in the specified L-arginine transport.

Casanello et al (2009) in the research involving HUVEC of normal andIUGR pregnancies, observed that the HUVEC of IUGR exposed to bothnormoxia (optimal amount of tissue oxygen that meets metabolic demands)and hypoxia, and HUVEC of normal pregnancy exposed to hypoxia, exhibitedreduced L-arginine transport, and reduced nitric oxide synthesis. Theyconcluded that the IUGR cells were either not responsive, or maximallyaffected by hypoxia.

But the above observations by Casanello et al can be the result of lackof both glucose (needed for synthesis of ATP for active argininetransport) and of oxygen in the IUGR affected vascular endothelial cells(HUVEC), whereas it was due to lack of only oxygen (hypoxia) inunaffected normal umbilical vessel endothelial cells (HUVEC) that canotherwise transport L-arginine (during normoxia) via active transportmediated by glucos that they are not deficient in.

Other positive effects of fetoplacental nitric oxide production—Wilcoxet al in 1989 reported reduced platelet (PLT) count in the cord bloodcollected at delivery from both normotensive and hypertensive patients,whose fetal Doppler umbilical cord studies exhibited high placentalvascular resistance. They hypothesized that there is increased PLTaggregation and consumption, as a result of the said placental pathologyof increased vascular resistance. Or, the primary pathology could be alocal imbalance in favor of excess thromboxane A₂ (responsible forpotent vasoconstriction and PLT aggregation) and consequent damage toplacental micro-structure, resulting in placental insufficiency(Nicolaides K. H and Campbell S, 1991). Nitric oxide apart from causingvasorelaxation, also acts on platelets to effectuate PLTanti-aggregation (Kniss D A. 2001). Essentially, in the above study ofWilcox et al there could be impaired Nitric oxide production, resultingboth vasoconstriction and also PLT aggregation/consumption.

It can be concluded that hypertonic glucose supplements not onlydirectly relieve hypoglycemia, but also by effectuating ATP-arginineinduced nitric oxide synthesis, indirectly inducevasculogenesis/vasorelaxation, and further alleviate the placentalvascular damage/impaired exchange of uteroplacental insufficiency, andso breaks the vicious cycle.

Effects of Glucose on D-Lysine Uptake, and the Placental Vasculogenesis—

Debatosh Datta (2007) observed that monomeric lysine was found to expandbiomass (cell population) at the least possible time compared to otherphysicochemical means. It was also observed that D-lysine can induceneovascular growth in all tissues types.

In the placental bed, D-lysine still has to be transported into the cellthrough active transport expending ATP, to exert such vasculogenesis. Incase of established trophoblastic failure, D-glucose supplement iscrucial to break the vicious cycle of placental insufficiency (as wasdescribed above in case of L-arginine deficiency), and to stimulatetrophoblastic villous elaboration, by supplying ATP needed for placentalD-lysine uptake.

9. The Positive Effects of Hypertonic Glucose Supplements on the Growthand Maturation of Vital Organ Like Fetal Brain

No organ in the developing fetus needs more glucose than the fetalbrain. Whereas all the tissues need glucose for energy, and as thecurrency of ATP (that is, for catabolic purposes), the fetal brain needsit as it's very building blocks (for anabolic purposes). So it can besaid that in the fetal organogenesis, in the brain's rapidly progressivearchitecture, glucose is the brick, whereas everything else, includingoxygen (ignoring it's gaseous form) serves only as it's cement.Moreover, glucose also has to additionally supply needed energy in thebrain, as elsewhere. In this context, the requirement of glucose in thedeveloping fetal brain as being enormous, is but anticipated. Unless oneexplores the biochemical architecture of the brain, it is hard to fathomthat all it's lipid components indeed took their origin from glucose,and it's quantity incorporated also can be unimaginable to a casualreader. It is for the reason that the brain's integral lipids are verylong chain fatty acids, the most important being the cerebronic acid,made up of 24 carbon atoms, that require ⅓^(rd) more of acetyl-CoAmolecules than the 16 carbon palmitic acid, the most synthesized fattyacid of the fetal body. Hence the most fundamental, and some so farunexplored issues of fetal brain's biochemical architecture, and thebest of glucose/oxygen economics warrant discussion here, especially inthe context of even normally prevailing relative hypoxia in-utero. Theinquiry that by what biochemical path ways the excess (in absolutenumbers) of glucose/oxygen expenditure by the fetus is normallycurtailed in this setting is crucial, as it was never explored beforewith the needed emphasis on the critical glucose/oxygen economy.

Symmetrical vs. asymmetrical fetal growth restriction—As defined in theintroductory paragraphs, fetuses or neonates whose estimated/attainedbirth weights are less than the tenth percentile are considered growthrestricted, as per the prevailing US guidelines, this being morestringent than the fifth percentile that is the standard cut off inother countries.

The IUGR fetuses or SGA babies are classified either as beingsymmetrically small, or asymmetrically small. This discretion isclinically significant that symmetrically grown IUGR fetuses or SGAinfants shall not be mistaken as premature.

-   -   1. Asymmetrically small—in these IUGR fetuses/SGA infants, the        length and the head circumference (HC) are normal or near        normal, whereas the abdominal circumference (AC) and the weight        are low. This is the brain sparing effect in a growth restricted        fetus, achieved by fetal auto-regulation that directs blood flow        preferentially to vital organs, the brain, the heart, and the        adrenals, at the expense of other organs including the kidneys.        This can be significant in causing fetal oliguria leading to        oligohydromnios.    -   2. Symmetrically small—in these fetuses/SGA infants, both the        abdominal circumference (AC) and the weight are low as in the        prior group, but so also are the head circumference (HC) and the        length.

At the onset of the third trimester the fetal head is normally larger incomparison to it's length and the abdominal girth, though the fetus'searlier striking tadpole configuration is less obvious at this time.Such disposition begins to change even more, starting 29^(th) week ofgestation when as a result of the initiation of fetal lipogenesis and ofthe glycogen storage in the liver, the abdominal girth/growthaccelerates. The head and the abdominal circumferences equalize by 34weeks, which however is not the case in the asymmetrically grown IUGRfetuses (Reiss R E).

The above discussion highlights that even in IUGR, the nature's defensesstrive hard to preserve the integrity of fetal vital organs, especiallythe brain. However, a failed potential for intellectual fulfillment isnot rare in this subset of pediatric population, as measured by low IQ,or as suboptimal educational attainment. In human, the myelination ofbrain is most rapid from the 7^(th) month of fetal life, the time whenthe fetal brain is most susceptible to the effects of under nutrition,for whatever reason. This is also the time the fetal IUGR usually makesitself manifest clinically. This makes the objective of diagnosing thefetal IUGR an imperative from early on, and the treatment of everypregnancy so afflicted a much sought after clinical endeavor so that nochild will be losing the innate potential it is genetically endowedwith.

Fetal Lipogenesis, and it's Role in Fetal Brain Development—

The human brain is predominantly made of fats, comprised of mainlyphospholipids and of glycolipids as the major structural components. Theoutlines of these biochemical entities were already specified in thesection of ‘Lipid Metabolism’, and they are herein elaborated.

The phospholipids of the brain are sphingomyelins, composed of—

-   -   1. Ceramide: it is made up of—        -   (a) Sphingosine—it is an alcohol analogous to glycerol            (glycerol is contained in the more familiar triglycerides of            adipose tissue), but it is a complex amino alcohol that            contains amino acid serine, and the palmitic acid.        -   (b) Fatty acid—it is made of cerebronic acid, a very long            chain fatty acid with the characteristic 24 carbon atoms,            and primarily derived from palmitic acid.    -   2. Choline, and    -   3. Phosphoric acid.

That is, the brain's phospholipids made of sphingomyelin, essentiallyconsist of: palmitic acid, serine, cerebronic acid, andphosphoryl-choline (choline & phosphoric acid).

The glycolipids of the brain are cerebrosides. They also containsphingosine-fatty acid combination (the ceramide) as in sphingomyelins,but a galactose moiety is attached to the ceramide instead of thephosphoryl-choline residue found in the sphingomyelins, and it'sstructural elements are as shown below—

-   -   1. Ceramide: is made up of—        -   Sphingosine (containing palmitic acid, and serine), and        -   Fatty acid (the cerebronic acid).    -   2. Galactose—a hexose carbohydrate, which is unique to the        glycolipids of the brain

That is, the brain's glycolipids made of cerebrosides essentiallyconsist of: palmitic acid, serine, cerebronic acid, and galactose.

By what was earlier discussed, it was made clear that 8 acetyl-CoA unitsor 4 glucose molecules are required in the biosynthesis of 1 molecule of16-carbon palmitic acid. Similarly, the biosynthesis of the 24-carboncerebronic acid needs 12 acetyl-CoA, or 6 glucose molecules asstructural elements, which however is achieved by chain elongation.

Microsomes are the site of chain elongation for fatty acids with evennumber of carbon atoms, starting from C₁₀ upward, using melonyl-CoA asthe 2 carbon donor, and NADPH+H⁺ as the reductant, in a manner similarto fatty acid synthesis, as described earlier with reference to thebiosynthesis of palmitic acid.

The Economics of Glucose-Oxygen in the Fetal Brain Fatty Acid Synthesis,and the Possible Path Way Involved for the Best of Glucose/OxygenSalvage— The Scheme of the Initiation of Lipogenesis ViaGlycolysis-Abbreviated Citric Acid Cycle (LGACC) in the Fetal Brain—

The synthesis of very long chain fatty acids in the fetal brain needssignificant expenditure of both glucose and oxygen. However, in thisanabolic process of fetal brain, staring from glucose molecules as theoriginators, the brain's fatty acid synthesis also generates moderateamount of ATP. It is for the reason that at the outset it involves theATP generating catabolic steps of glucose in the pathway of glycolysis,yielding the acetyl-CoA that are needed as the building blocks ofpalmityl-CoA. It also needs to be duly noted at this point that thebrain's glycolipids and phospholipids contain both cerebronic acid (of24 carbon units) and palmitic acid (of 16 carbon units), which togetheramount to a need of a total of 20 acetyl-CoA (and of 10 glucosemolecules) altogether, for the formation of 1 molecule of either aglycolipid or of a phospholipid. But in the following discussion thefocus is confined to the synthetic requirements of cerebronic acid, thelongest chain fatty acid, because for the needed calculations theexemplified cerebronic acid can serve the purpose.

The initiating steps of the lipogenesis via Glycolysis-AbbreviatedCitric acid Cycle (the LGACC) in the fetal brain—The fetal Lipogenesisvia Glycolysis-Abbreviated Citric acid Cycle (LGACC) is shown in theFIG. 6. The Acetyl-CoA (148) formed from pyruvate (146) in themitochondrion (172) can not penetrate the mitochondrial membrane (150)to enter the cytosol (152), the site of fatty acid synthesis.Accordingly, it has to enter citric acid cycle to form citrate (156)which can get out into the cytosol (152), as virtually only twocarbohydrate intermediates, the α-ketoglutarate and the citrate canfreely leave the mitochondria without permeability barriers. In thecytosol (152), the citrate (156) is cleaved by ATP-citrate lyase (158)to acetyl-CoA (160) and oxaloacetate (162), with also consumption of 1ATP that is transformed to ADP. The acetyl-CoA (160) so reformed canengage in cytosolic free fatty acid (142) synthesis. The reformedoxaloacetate (162), just as in the later part (the cytosolic part) ofmalate shuttle can react with the NADH+H⁺ (164) that is beingcontinuously formed in the cytosol (152) via glycolysis (144) to formmalate (180) (catalyzed by cytosolic malate dehydrogenase, 192) that canenter the mitochondrion (172), in exchange with some more of citrate(156) getting out of the mitochondrion (172) through the citratetransporter (CT) (166), so facilitating the pathway of lipogenesis (176)on-going. Malate (180) can only exchange with citrate (156) in thistransport. Malate (180) then enters the (abbreviated) citric acid cycle(154) to form oxaloacetate (174) while also reducing NAD⁺ (168) toNADH+H⁺ (170) (that can generate 3 ATP) as in the usual manner of thefinal step of the full-fledged citric acid cycle. This is the‘abbreviated citric-acid cycle’ (154) that accomplishes the initiationof fatty acid (142) synthesis in the tissues specializing lipogenesis,as the brain. It is made possible by the incorporation of glycolysis,the citrate forming first step, and also the last step of citric acidcycle, further incorporating the integral functional aspects of ‘protontransfer’ into the mitochondrion from the cytosol, otherwise normallyachieved in the cell by the malate shuttle. Each citrate molecule(needed for fatty acid synthesis) getting out of the mitochondria needsmalate in exchange coming in (as needed substrate pair). Only in 1citrate diversion (elaborated below) into FFA synthesis, malate shuttleis needed for the transfer of the other NADH+H⁺ (164) generated from 1molecule of glucose.

FIG. 6 also shows HMPS (182), the pathway of carbohydrateinter-conversion (involving D-glucose, 140), that continuously suppliesNADPH+H⁺ (184) to the free fatty acid (142) synthesis, wherein it isoxidized to NADP⁺ (186) to reenter the shunt. FIG. 6 further shows CO₂(188) being used, and CO₂ (190) being subsequently liberated during thefree fatty acid (142) synthesis.

The abbreviated citric acid cycle in tissues active in lipogenesis, isonly speaking of the ultimate fate of each and such majority of glucosemolecules being combusted in the above manner (though otherwise destinedfor a full-fledged citric acid cycle), and not of the whole scene ofmetabolic cycles/activity going on in the cell or it's mitochondria,because as a whole, there can be imperceptible merge of both path ways,as some full-fledged citric acid cycles are invariable in any cell.

The question that arises at this point is whether both citrate moleculesgenerated from a single molecule of glucose are diverted to fatty acidsynthesis, or one will continue into full citric acid cycle to generateneeded ATP. Due to the sheer number of acetyl-CoA molecules needed foreach molecule of cerebronic acid generated, it seems plausible that bothcitrate molecules are diverted into fatty acid synthesis that accountsfor significant glucose/oxygen salvage. The economics of both glucoseand oxygen (in absolute numbers) show dramatic difference if bothcitrate molecules are diverted to fatty acid (cerebronic acid)synthesis, as opposed to only one is diverted, the other being continuedthrough the full-fledged citric acid cycle, generating ATP in the usualmanner.

The ATP Yield Vs. O₂/Glucose Expended in Either 1 Citrate Diversion, or2 Citrate Diversion is Explained as Follows—

2-citrate diversion—in this process, 8 ATP are generated via glycolysiswith 1 molecule of glucose (with 1O₂ expended). So also, 6 ATP aregenerated when 2 acetyl-CoA molecules are formed (with 1O₂ expended).The two citrate molecules will be cleaved to 2 molecules ofoxaloacetate, and 2 molecules of acetyl-CoA in the cytosol byATP-citrate lyase. The 2 acetyl-CoA molecules will participate in fattyacid synthesis, whereas the 2 molecules of oxaloacetate in the cytosolwill be reduced to malate by 2 NADH+H⁺ (generated via glycolysis), as inthe last steps of cytosolic malate shuttle. The 2 molecules of malatewill return to mitochondria to form 2 molecules oxaloacetate throughmitochondrial malate dehydrogenase. However, no ATP can be credited forthis reaction of the last step of citric acid cycle, as thetransformation of oxaloacetate to malate is accomplished by using thereducing equivalents generated in glycolysis, and as in a malateshuttle, the 6 ATP generated via the mitochondrial malate dehydrogenaseare accounted to glycolysis, and not to the citric acid cycle. There isno complete revolution of the typical citric acid cycle that generatesanother molecule of malate. Accordingly, the total ATP generated in thisprocess via glycolysis-citric acid cycle of 1 molecule of glucose is 14(8 ATP from glycolysis, and 6 ATP during the formation of 2 acetyl-CoA),expending a total of 2 O₂. For 1 molecule of cerebronic acid to besynthesized, the fetus spends 6 molecules of glucose (and 12 ofacetyl-CoA), and 12 molecular O₂, generating 84 ATP in the process (seetable-4).

1-citrate diversion—in this process, one-citrate molecule continues intothe full-fledged cycle to produce 12 additional ATP, with an over-alltotal of 26 ATP generated with 1 molecule of glucose, 4 oxygen beingexpended in the process. However, with a total of 12 glucose moleculesneeded for 1 molecule of cerebronic acid to be synthesized, the fetus isbound to spend 48 molecules of O₂, however with 312 ATP generated (seetable-4).

Table-4, Glucose/O₂ spent vs. ATP generated via glycolysis-abbreviatedcitric acid cycle during the synthesis of 1 molecule of cerebronicacid—involving either 1 or 2 citrate diversion into FFA synthesis; andfurther comparison of ATP yield with full-fledged glycolysis-citric acidcycle

net ATP Citrate acetyl- generated in ATP/ diversion into Glucose CoA O2glycolysis - O2 lipogenesis spent spent spent citric acid cycle ratio2-citrate diversion - 6 12 12 84 7 1-citrate diversion - 12 12/12 48 3126.5 Glucose/O2 spent via full-fledged glycolysis-citric acid cycle 1 2 638 6.3

In the above table, with reference to 1-citrate diversion, 12/12acetyl-CoA signifies that 12 of them are diverted to fatty acidsynthesis, whereas 12 are continued into the full-fledged citric acidcycle.

With 1-Citrate Diversion, the Theoretically Probable Absolute Excess ofGlucose/O₂ Spent, and Excess ATP Generated, Compared to 2 CitrateDiversion, is—

Glucose spent 2 times more (200% more) O₂ spent 4 times more (400% more)ATP yield 3.7 times more ATP (per 1 O₂ yield) 6.5 during 1-citratediversion vs. 7 during 2-citrate diversion (6.5/7) that is, 7.1% more ofATP production during 2-citrate diversion.

Comparison with the full-fledged glycolysis-citric acid cycle—Comparingthe above to the ATP gain/oxygen expenditure via the regularfull-fledged glycolysis-citric acid cycle of a single glucose molecule(when 38 ATP are produced per 6O₂), it can be noted that the yield per1O₂ is 6.3 ATP (6.3/1O₂), whereas during 2-citrate diversion the yieldper 1O₂ is 7 ATP (7/1O₂). This seems optimistic, because though glucosespent during fetal neuronal lipogenesis via 2-citrate diversion is 2.7times more to generate similar ATP as the regular citric acid cycle(that is, 6 glucose generating 84 ATP vs. 1 glucose generating 38 ATP),the oxygen expenditure is lowered by 10% for similar ATP yield.

It can also be deduced that the D-glucose supplements enormously aidfetal brain development while the oxygen requirements are reduced by 10%for similar generation of ATP, whereas the absolute O₂ requirementitself is reduced by 400% by the rapid anabolic process accomplished ina set unit time (time vs. achieved glucose supply/lipogenesis) by2-citrate diversion (as in a well-fed state), wherein the absoluteglucose requirements are also reduced by 200%. This deduction is ofextreme significance when one can be concerned or skeptical aboutpossible adverse effects of prevailing hypoxia in the setting oftherapeutic D-glucose supplements. The 400+10% O₂ salvage is apart from33%+ of oxygen salvage achieved by curtailing beta oxidation of fats,and by preventing the fetal body muscle protein utilization for energyrequirements (the ATP/O₂ salvage being more from the latter). It may benoted that the activity of ATP-citrate lyase is increased duringcarbohydrate availability, induced by insulin.

The above numbers need additional comment. As was clarified above,following the combustion of a single molecule of glucose, the acetyl-CoAdiverted to fatty acid synthesis is doubled in 2-citrate diversion, sothat lipogenesis can be achieved rapidly and effectively withdrastically less glucose/oxygen expenditure (in absolute numbers) evenin the situations of relatively low glucose/oxygen availability.However, this is achieved at the expense of high number of ATP thatcould have been otherwise generated by 1-citrate diversion.Nevertheless, it may not be overlooked that the first and the foremostpriority during fetal organogenesis is the lipogenesis needed inexponential amount in the rapidly developing fetal brain, and everythingelse must be concerted in that direction. However, for the sheer numberof acetyl-CoA needed for glycolipid/phospholipid synthesis, ATP is beinggenerated in significant numbers from glycolysis alone which path way isinvariable for the needed acetyl-CoA, and in this unique context, thecitric acid cycle, though esteemed for it's economics, is rather awastage, and can be mostly by-passed. It also may be noted that thefetal brain compensates for the absolute number of ATP lost vialipogenesis by the exceeding amount of glycolysis, but spending less ofoxygen, and more of D-glucose, which is supplied in this therapeuticendeavor. It also follows that the fetus can engage in some of thefull-fledged citric acid cycles only when the ATP requirements withinthe brain are more (that is, it relays in the brain's energy vs. growthrequirements).

The Energy Versus Growth Requirements within the Fetal Brain—

Fetal growth and maturation—The fetal brain's growth requirements areenormous, whereas energy requirements are substantially less compared toit's adult counterpart. It merely means to say that the fetal brain isquiescent, but not inert. Only it's heart can surpass the brain in theamount of ongoing functional activity in quantity and quality, neededfor continued survival in it's unpredictable aquatic environment. Thebrain's sympathetic and parasympathetic circuits are very active even atthis stage, as the heart rate should respond by beat to beat variationto the hypoxic insults, or to the hypotensive episodes, the inputcarried by para-sympathetic afferent. Hence, the brain'sneuro-transmitters must be synthesized extremely rapidly. The fetalheart rate being double that of an adult, the brain's basal sympatheticout flow is also very active and very rapid. The fetus in addition hasvery potent brain-endocrine system, the hypothalamo-pitutary axis beingfunctional from very early on, that controls the adrenals, the thyroid,and the gonads, in terms of both growth and function. While such growthis unsurpassed, the brain's cortical functional activity, and theactivity of the neuronal circuits essential for volitional motoractivity are minimal, making it's ATP requirements far less incomparison to the growth requirements. It can be aptly said that thefetus with it's uncomparable growth potential, is not only a feedinglarva, but also a resting pupa, and there needs to be a very finebalance achieved between it's growth and it's gain of ATP.

Because a sheer number of acetyl-CoA units are needed/produced for fetalbrain development, and the process being also accompanied by moderateATP yield that is proportional to the normally low fetal activity/energyrequirements, it is prudent to say that the abbreviated citric acidcycle with predominant 2-citrate diversion is the main path way, and thefull-fledged citric acid cycle (with more glucose-oxygen expenditurewith high ATP yield) as needed, being the additional path way in thefetal brain. As per the popular belief some full-fledged citric acidcycles are invariable, one reason among the few being—for the endproducts of protein break down to merge in the cycle, as there is activeamino acid metabolism also in the brain (where there is seemingly onlyof glucose trafficking, and of lipid manufacturing) for the synthesis,and for the rapid turn-over of multitude of neurotransmitters like—GABA,epinephrine, norepinephrine, acetylcholine, dopamine etc. The earlierdiscussion was about the merits of 2 citrate vs. 1 citrate diversioninto lipogenesis, but the significant amount of ATP consumed later forlipogenesis itself is unchanged, starting from citrate cleavage. All theanabolic processes are energy consuming. During the nine months of fetalintrauterine stay of which pregnancy is about, most of the energy isdeservingly devoted for such anabolic needs.

What Makes the Glycolysis—Abbreviated Citric Acid Cycle in the FetalTissues Engaged in Lipogenesis a Possibility, and Yet Generates any ATPat all—

It can be said that the citric acid cycle is an ultimate testament ofthe body's achievement in efficiency and economy. However, a substantialnumber of glucose molecules after glycolysis can by-pass thefull-fledged cycle, as long as the concerned reducing equivalent (the2H⁺ or protons) generated via the glycolytic process are connected tothe mitochondrial respiratory chain at least through one step of thecitric acid cycle to generate ATP. Thus it is obvious that no glucosemolecule can short-cut or by-pass any of the steps of glycolysis,whereas by-passing and short-circuiting with ease can be done to themany steps of citric acid cycle, and yet generate ATP. In the case ofglycolysis-abbreviated citric acid cycle, the step involvingglyceraldehyde 3-phosphate dehydrogenase of glycolysis is connected tomitochondrial respiratory chain through the last step of citric acidcycle (involving mitochondrial malate dehydrogenase) through maneuverssimilar to the malate shuttle, and the subsequent step involving thepyruvate dehydrogenase complex being mitochondrial, is directlyconnected to the mitochondrial respiratory chain. Full-fledged citricacid cycle is geared towards maximal efficiency of glucose combustion,but by all means it's many steps though not all steps, can be by-passed.So it can be clearly stated that the abbreviated citric acid cycle thatmany glucose molecules must pursue is fully compatible with cellfunction in the sites of active lipogenesis in-utero. It is alsocompatible with sufficient ATP production even while only 14 ATP arebeing produced with each abbreviated cycle, as it's sheer numberaccounts to a substantial total.

Is predominant abbreviated citric acid cycle (ACC) compatible withoptimal cell function ? This question can be answered by criticallyexamining the intermediates of the citric acid cycle. The most importantof these are citrate, malate, α-ketoglutarate, and the succinyl-CoA thatare intimately and essentially connected to other vital metabolic pathways. In the ACC, the citrate and the malate are the targetintermediates, and hence the focus can be diverted to the other two. Theα-ketoglutarate is essential for protein metabolism, for it's pivotalrole involving the deamination of many of the α-amino acids. The braincells also need it for such process, for the many activities that go onin the brain involving the amino acid metabolism. The Dopamine, theepinephrine, and the norepinephrine are synthesized in the brain fromtyrosine, but are metabolized with no involvement of α-ketoglutarate.GABA is synthesized from L-glutamate, and it's metabolism in the braininvolves the need of α-ketoglutarate. The succinyl-CoA is essential forheme synthesis, but obviously it's need is more in the erythropoitictissues, and not necessarily in the sites active in lipogenesis.

The Allosteric/Regulatory Inhibition Controlling the Cell's Own ATPSynthesis—

In the tissues specializing in lipogenesis, such function predominates,and the cell is capable of controlling it's own ATP production only asneeded, and no more.

1. The steps involving combustion of food stuffs, and of the flow ofreducing equivalents in the respiratory chain of mitochondria foroxidative phosphorylation are step-wise, allosterically controlled andefficient, rather than explosive or wasteful (Mayes P A).2. In the mitochondria, the oxidation and phosphorylation are tightlycoupled (Mayes P A). That means, with out the availability of ADP forphosphorylation, the oxidation expending molecular oxygen can notproceed. The availability of ADP is in turn controlled by the body'sutilization of ATP, thus reducing it to ADP. Essentially, when there isadequate availability of ATP within the cell for needed biochemicalactivities, and no more ATP is needed (as can be evident by the relativeunavailability of ADP within the cell), no more of it is produced in themitochondria.3. The function of ADP/ATP transporter which permits entry of cytosolicADP into, and the ATP out of mitochondria is rate limiting. The overallrate of a simple or complex series of biologic reactions is determinedby the slowest step in such series which is rate limiting to the entireseries (Guyton A C). Under a resting condition as the fetus is, theconcentration of ADP in the cells is very low, and the chemicalreactions that depend on ADP, the most important being oxidativephosphorylation with ADP as it's substrate, can be slow also, thus ADPbeing the rate limiting factor for all energy/ATP producing metabolicpathways of the body.4. Insulin, increased during glucose availability and satisfied ATPneeds (a scenario helped by D-glucose supplements) stimulateslipogenesis in the fetus, the most important effect being increasing theactivity of acetyl-CoA carboxylase needed for synthesis of melonyl-CoA,the building block of fatty acids. Such diversion curtails the citratecontinuity into the citric acid cycle, that in turn prevents oxidativephosphorylation.5. The fatty acid synthase complex, and the acetyl-CoA carboxylase arethe enzymes unique for their ability to adapt to the body's immediaterequirements. Insulin increased during glucose availability and hencesatisfied ATP needs (a scenario helped by D-glucose supplements) alsoplays a role in inducing the gene expression of these enzymes, and thuscausing their biosynthesis. This enhances the fetal brain's anabolicprocess, and prevents the ATP generating catabolic path ways.6. The activity of ATP-citrate lyase is increased during carbohydrateavailability, and decreased during it's lack. It is also induced byinsulin. This state of affairs enhances lipid anabolism, and diminishesthe glucose/citrate catabolism (a scenario also helped by D-glucosesupplements).

Serine needed for the phospholipid/glycolipid synthesis is synthesizedby the intermediate of glycolysis—Serine, the only amino acid needed forbrain phospholipids/glycolipids is synthesized by 3-phosphoglycerate,the intermediate of glycolysis. Thus the predominantglycolysis-abbreviated citric acid cycle in the fetal brain isself-sufficient in generating also other elements needed for fetal braindevelopment. One glucose molecule is utilized for generating 2 moleculesof serine. This adds one more molecule of glucose expended for 2molecules of brain ceramide synthesized.

The Maternal Fatty Acid Transfer—

At this point, after analyzing the tremendous amount of fatty acid ‘layover’ that is to be rapidly accomplished in the fetal brain during thelast months of it's life in utero, it is also a legitimate issue todiscuss if the fetus must solely engage in it's fatty acid synthesis, orif there is significant placental transfer of maternal fatty acids to beincorporated to form the longer chain fatty acids of the brain, or theadipose tissue triglycerides, and if so, by what proportion? The answerseems to be difficult. As was mentioned, the free fatty acid (FFA)transfer across the placenta is by simple diffusion as per theconcentration gradient, and is compounded by the fact that there are nocellular components on the maternal part of the placenta, the wholematernal compartment being pools of blood, whereas the fetal side ismade of only the syncytio-cyto-trophoblast and the fetal vessel wallthat the fatty acids have to maneuver through. This anatomical easeaccomplishes significant fatty acid transfer needed for the human fetus,whose lipid lay-over in the brain is significant for it's voluminoussize to be ultimately achieved. The immediate fatty acid anabolic ‘layover’ in needed sites probably also accounts for the fetus maintaininglower FFA concentration contributing to higher gradient for continuedsimple diffusion through the placental interface. Such rapid fetallipogenesis is in contrast to heightened maternal lipolysis coincidingwith such time, to maintain ongoing high maternal-fetal FFAconcentration gradient/transfer.

There is support for such theoretical ease of placental fatty acidtransfer. It was demonstrated directly in the sheep (Van Duyne et al,1960). When radioactive fatty acids were injected intravenously into themother, they appeared in fetal circulation in few minutes. It can alsobe confirmed by the observation that the essential fatty acids werefound in the adipose tissues of the new born infants (Bagdade and Hirsh,1966

It was hypothesized by past researchers, that the fatty acid compositionof fetal adipose tissue shows that the synthesis de novo assumes greatersignificance in the later part in-utero. This was evidenced by the factthat towards the end of fetal life, the proportion of linoleic acid (anessential amino acid to be supplied by the mother) in the fetal adiposetissue decreases, and the proportion of palmitic acid (that can besynthesized by the fetus from acetyl-CoA via melonyl-CoA path way)increases, and at birth, the adipose tissue of the neonate contains onlyone tenth of linoleic acid, and twice the amount of palmitic acidcompared to the adipose tissue of the adult. Accordingly it washypothesized that synthesis de novo assumes greater significance, whichwas thought to be further supported by the fact that such fatty acidcomposition of the neonate closely resembles that of animals fed withhigh carbohydrate, and poor fat diet (N. B. Myant).

The above observations and conclusions by past researchers may inferthat there can be predominant de novo fatty acid synthesis by the fetusat term, but it may not necessarily represent the specified proportion,in the manner implied. It is due to the following reasons, as put forthby the author inventor, validated by laws governing the kinetics ofdiffusion. Palmitic acid is synthesized by the fetus, and linoleic acidis not, but it does not rule out or clearly quantify how much palmiticacid is also supplied by the mother. The non-essential fatty acids aretransferred also across the placenta, just like the essential fattyacids, without any differentiation (Leslie Myatt). It also does not ruleout more of palmitic acid transfer. Maternal lipogenesis increases inlinear fashion to a maximum at 25 weeks, when it continues as a plateauto term. Maternal lipolysis predominates in the later part of pregnancy,when there is ongoing de-esterification, and of fat mobilization fromthe past-laid maternal fat depots, by the action of HPL. It can raisethe circulating maternal free palmitic acid level that can cross theplacenta by diffusion, through concentration gradient. The FFA levelsreach a maximum of 4-5 times of non-pregnant levels in the later part ofpregnancy. At 37-40 weeks of gestation, the maternal FFA levels increaseexponentially by 60%. In an adult on balanced diet (like a pregnantwoman), the adipose tissue subcutaneous fat contains oleic acid 47% (18carbon mono-unsaturated fatty acid), palmitic acid 20% (16 carbonsaturated fatty acid), and linoleic acid 11% (18 carbon unsaturatedfatty acid). The adipose tissue of new born infant contains palmiticacid as 40%, oleic acid 25%, and linoleic acid 1% (Hirsch, 1965). Thefatty acids pass through the lipid bilayer of cell membrane by simplediffusion, and as per the kinetics of diffusion, with the diffusion ratebeing inversely proportional to the molecular weight of a molecule, itis possible that though the 18-carbon unit oleic acid is present inhigher concentration in the maternal fat depots and in the maternalblood, it's diffusion across the placenta must be slower, compared tothat of the 16-carbon unit palmitic acid with lesser molecular weightand smaller chain length, which after entering the fetus can be directlylaid down to form the triglyceride molecules of the fetal sub-cutaneousadipose tissues. The proportion of linoleic acid in maternal plasma islower, and in addition, it's molecular weight is higher, and the chainlength longer than that of the more predominant palmitic acid.

It can be reasonably concluded that in a normal fetus the significantamounts of the maternal fatty acids are mostly laid down in the mannertransferred from the placenta, and the fetus need not synthesize allthat is required. Manipulation of maternal diet can also proportionallyincrease such transfer. Above all, as discussed, nature's device ofmaternal lipolysis through HPL of pregnancy is important and purposeful,as such scheme is also coupled with maternal utilization of FFA insteadof glucose for energy, as the latter also needs to be diverted to thefetus. It also is worth noting that maternal high carbohydratediet/circulating glucose can generate more triglycerides of her adiposetissues than the high fat diet (though the latter can directlycontribute to the rise of circulating FFA in the maternal blood to beused as her fuel), most of the maternal tissues being resistant toinsulin effects, whereas her fat depots and the placenta are not.

Maternal D-Glucose Supplements can Substitute for/Correct the FetalOxygen Lack Via Maternal Lipogenesis/Lipolysis, Resulting in ‘Ready-MadeFFA’ Transfer—

It is clear from the foregoing paragraph that the maternal glucose isthe raw material for the maternal fat depots from early on in pregnancythat is mobilized later on when the fetal demands are more in it's phaseof lipogenesis. It signifies the needed maternal circulatingcarbohydrate (by IV or dietery supplements) as the indirect element (asmaternal FFA) to be incorporated during fetal lipogenesis, and as thedirect element of optimal maternally derived circulating glucose in thefetus that also engages in de novo lipogenesis. That means, the mothersynthesizes FFA to transfer them ‘ready-made’ when the fetus is in it's‘speed mode’ of lipogenesis later on, obviating a tremendous need ofglucose/oxygen by the fetus. At the conclusion, it is worth stressingthat D-glucose substitutes for O₂ lack, with an oxygen salvage in thefetal brain as—(a) 400% of absolute oxygen salvage by 2-citratediversion (instead of one) during sufficient glucose availability, forthe rapidly accomplished fetal neuronal lipogenesis (or lipogenesis ingeneral), and an additional 10% ATP/oxygen salvage through LGACC; (b)33% by obviating the brain's utilization of FFA as fuel; (c) >33% bypreventing ATP expending amino acid utilization which in turn needs moreof full-fledged glucose/O₂ expending citric acid cycles also; (d) fetalgain of predominantly D-glucose-derived maternal FFA, thus obviating anotherwise exceeding fetal need of ATP/O₂. Such deduction helps toalleviate one's possible concern that hypertonic D-glucose supplementsseem disproportionately high compared to the amount of oxygen the fetuscan avail. The glucose needed in this context is indeeddisproportionately high in the rapid fetal lipogenesis compared to theoxygen needed, the glucose expenditure being 2.7 times more, but theoxygen needed for the same amount of ATP synthesis is 10% less than whatis spent by the tissues elsewhere.

10. Improvement of ATP Synthesis, the Ultimate Key, as the UbiquitousNeed for all Life Forms, and for all Life-Sustaining SubcellularActivities

It was sufficiently stressed on multiple occasions how the citric acidcycle of the D-glucose metabolism is life sustaining through it'spivotal role in ATP production. During fetal hypoglycemia and hypoxiacitric acid cycle will cease to be operative, and the D-glucosesupplements improve not only fetal hypoglycemia but also fetal hypoxiato a significant extent as clearly evidenced by the foregoing objectivedata. It is also sufficiently clear that no biological function can everhappen without ATP in the fetus, and that the lack of ATP by thecessation of citric acid cycle can culminate in death, and lack ofglucose can culminate in the cessation of the citric acid cycle. As atranslation of what is herein deduced, it can be stated—for the fetusin-utero ‘glucose is life’, and life is being given to the fetus by it'ssupplements.

Fetal Adipose Tissue Lipogenesis—

Acquisition of fat in the subcutaneous adipose tissues of the fetus inthe later months of pregnancy has multiplicity of purposes:physiological awakening of thermoregulation soon after birth to meet theunpredictable temperature fluctuations ex-utero, and the heat requiredbeing provided by the adipose tissue; the relative fetal hypoglycemiadue to abrupt cut off of maternal provisions, and explosion of physicalactivity in all parts of the newborn including vigorous crying, such anabsolutely vital activity in high tempo at birth and after needingtremendous energy, and the neonate left to be solely relying on burningit's fat stores.

With the subcutaneous fat depots being sub-optimal, a significantlydeprived IUGR baby devoid of baby-fat appears like a ‘little adult’ witha typical ‘wizened look’ which is not hard to discern.

The amount of glucose needed for the adipose tissue lipogenesis can becomprehended by acknowledging the fact that one molecule of triglyceride(TGD) is formed by the esterification of one molecule of glycerol withthree molecules of free fatty acids. A new born infant has predominantly16-carbon atoms palmitic acid (40%), or 18-carbon atoms oleic acid (25%)in it's subcutaneous tissues. Accordingly, the three molecules of freefatty acids in the fat depot TGD need 24-27 acetyl-CoA or 12-13.5glucose molecules, and inclusive of the ½ molecule of glucose needed forglycerol synthesis, just one TGD molecule needs 12.5-14 of glucosemolecules in it's formation. Based on such high toll on the availableglucose, it seems that even in normal fetus, acquisition of FFA from thematernal compartment is invariable addition to fetal de novo synthesis.It was already noted that glucose expenditure in absolute amount iscurtailed by 200%, and the absolute oxygen needed during exclusive fetallipogenesis is 400%+10% less, and such saving provision is applicable tothe lipogenesis in the subcutaneous adipose tissues also, that isstrongly in favor of therapeutic D-glucose supplements.

The Other Important Source of Fetal Oxygen Supply: The Amniotic Fluid

It seems rather phenomenal that the fetal umbilical vein alone cansupply all the needed oxygen for the enormous growth accomplished by thefetus through a mere span of ten lunar months. It makes one contemplatethat there must be other source(s) so far not suspected. The fetalaquatic environment can be such source. It seems against nature'sintension that the amniotic fluid being the sole fetal world can be adormant environment, rather than an active contributor to the fetalgrowth and maturation in every possible manner. After all, the endlessoceans can accommodate enough oxygen to support it's vast aquatic life,and it is a testament to the fact that water is a satisfactory carrierof oxygen, as our focus of interest at this point is towards themyometrial and decidual interstitial fluid as a suitable milieu foroxygen transit, though through a short span of distance. Theextracellular water of the vertebrates and the primate humans is knownto be similar to the electrolyte composition of the waters of the oceans(Goldberger E, 1980), such biological property reflective of the vastnature preserved through billion years. Additionally, it was alreadyconfirmed by past researchers that AF does contribute to, and isessential for optimal fetal growth. It was also observed that the PCO₂of the AF is very high (R. Lisle Gadd, 1970, and Nicolaides et al 1989),probably in the range of 48 mm/Hg (Rooth et al), mostly due to thevirtue of it's high solubility/diffusion coefficient. To substantiatethe fact that AF can be a significant source of fetal oxygen supply, itis important to understand the dynamics of oxygen and CO₂ carriage inthe pregnant/non-pregnant systemic circulation, their release at thelevel of placental intervillous space/tissue capillaries, along with thedynamics of the partial pressures of oxygen/CO₂ at these sites. Thecomplex biological principles of the terrestrial lifeforms are gearedtowards more efficiency of oxygen carriage/supply, by virtue of it'snatural gaseous existence in the lungs than as per it's existence inlowered proportion in the aqueous ecosystem of the oceans. How ever, thefetal activity in it's fluid world in solitude is after all far lessthan that of the innumerable aquatic forms of the oceans, restlessly inmotion, yet gaining their fair share of oxygen.

The pulmonary gaseous exchange in a healthy adult—the partial pressureof oxygen (PO₂) in the alveoli is 104 mm/Hg. The pulmonary bloodequilibrates well with the alveolar gases, and hence the purified bloodleaving the lungs also has the same PO₂ of 104 mm/Hg. However, after itis joined by the bronchial venous blood, it is reduced to 95 mm/Hg.Hence, essentially the systemic arteries terminating into the arteriolesand capillaries have the same PO₂ of 95 mm/Hg.

The gaseous exchange at the interstitial spaces in a healthy adult—atthe tissue interstitial spaces the PO₂ is 40 mm/Hg with effectivefiltration gradient of 55 mm/Hg at the arterial capillary level. Thecapillary and venous blood PO₂ equilibrate effectively with that oftissue interstitial space, and accordingly, the venous blood leaving thetissues has PO₂ of 40 mm/Hg. In fact, in the interstitial spaces the PO₂could be more, when the rate of blood flow is increased. The blood flow,if increased by 400%, as of the muscle during muscular exercise, the PO₂in the interstitial fluid can increase from 40 to 66 mm/Hg, and amaximum of even 95 mm/Hg can be achieved by markedly increased bloodflow (Guyton A C). The uterine tissues during pregnancy withsignificantly increased vasculature, and exceeding metabolic activitycan attain higher interstitial fluid PO₂, which however, was notexplored as a targeted issue by past researchers.

Diffusion at the intervillous spaces where the fetal umbilical vesselsterminate—the uterine artery has a PO₂ of 95 mm/Hg. However, due to thesinusoidal architecture of the maternal placental compartment conformingto an arteriovenous shunt, the PO₂ of the uterine spiral arteries fallto a level of 30-35 mm/Hg in the sinusoidal spaces (Pritchard J A. etal) (however, in the uterine vein, the PO₂ again raises back to 40mm/Hg, as in the rest of the maternal systemic venous circulation,overcoming the placental shunt effect). The foregoing set of numbers,and other similar data that follows, are shown in table-5.

The fetal umbilical artery (carrying fetal deoxygenated blood) has a PO₂of 15 mm/Hg which after exchange with the maternal blood rises to only27 mm/Hg in the umbilical vein (carrying fetal oxygenated blood). TheBohr effect can be summated as—‘the hemoglobin-oxygen binding affinityis inversely proportional to the it ion concentration, and also to thatof the CO₂ concentration’. Accordingly, in the placental sinusoids thereis shift to the left of fetal oxygen-hemoglobin dissociation/associationcurve (such shift being a reflection of higher O₂-hemoglobin affinity orassociation) due to: (a) and (b) effectuated by Bohr effect that can bedescribed as—(a) low PCO₂ of the sinusoids to start with (due tomaternal hyperventilation) causing net higher diffusion of CO₂ (whosediffusion coefficient is 20 times that of O₂) from fetal blood, thusreducing the CO₂ of the fetal blood proportionally; (b) fetal bloodbecoming more alkaline as a result of (a); the (a) and (b) resultingfrom Bohr effect further aided by (c) low affinity of fetal hemoglobinto 2,3-DPG (2,3-diphosphoglycerate) (the 2,3-DPG causes stability ofdeoxyhemoglobin). Due to left-ward shift of fetal hemoglobin-oxygendissociation/association curve in the placental sinusoids due to (a),(b), and (c), the fetal hemoglobin can carry more oxygen even at a lowPO₂ of maternal sinusoids.

However, based on the plotting of oxygen-hemoglobindissociation/association curve that is sigmoid, due to the prevailinglow PO₂ in the sinusoids, despite the shift to the left of the oxygendissociation/association curve, the fetal hemoglobin oxygen saturationwill be only 68% (Longo 1972), and not 97% (the saturation of hemoglobinin the lungs), as the PO₂ of 30-35 mm/Hg in the sinusoidal spaces doesnot correlate with the plateau of the oxygen-hemoglobindissociation/association curve in the manner the plateau of theoxygen-hemoglobin dissociation/association curve correlates at thealveolar spaces with the PO₂ of the alveoli as high as 104 mm/Hg,facilitating maximum hemoglobin saturation. However, this low PO₂ of 27mm/Hg of the fetal arterial blood is still effective for the reason thatonly 5 mm/Hg of PO₂ is sufficient to support the oxidative metabolicfunction of the cell, as a function of cytochrome oxidase (Rodwell V Wet al).

The PCO₂ of the umbilical vessels show interesting values. The umbilicalartery carrying fetal impure blood has PCO₂ of 48 mm/Hg, and theumbilical vein carrying the fetal oxygenated blood has a PCO₂ of 43mm/Hg. The uterine artery PCO₂ is 32 mm/Hg during pregnancy due tomaternal hyperventilation, and after an exchange with the fetal blood,it increases in the intervillous space to an average value of 38 mm/Hg.

As shown in table-5, the above equilibrated PCO₂ values of placentalexchange show a marked difference from the equilibrated values of thesystemic circulation of the non-pregnant controls, where the PCO₂ of thevenous blood indeed equilibrates to 45 mm/Hg of the interstitial fluid,and the pulmonary deoxygenated blood is also equilibrated with that ofthe alveolar air, the latter happening normally with in a fraction of amillimeter, and within the ⅓^(rd) transit time of the pulmonarycapillary blood (Guyton A C). It is due to the high diffusioncoefficient of CO₂, and because of the fact that the PO₂ in the alveolibeing very high, falling in the plateau range of the O₂ association(thus maximizing the Haldane effect of CO₂ release). At the placentallevel, the explanation is not as easy or straight forward, for theequilibration that is seemingly not attained. The umbilical vein PCO₂seems to have not equilibrated with the maternal sinusoidal PCO₂ despitehigh diffusion coefficient of CO₂, and a lower prevailing maternalsinusoidal PCO₂, a more suitable milieu than that of the capillary endof the systemic circulation. In fact, there is no validbiochemical/physiological explanation to put forth, for failure of theumbilical vein PCO₂ to be lowered, as expected. But the situation maynot be what it seems as. Due to very high diffusion coefficient of CO₂,the amniotic fluid (AF) PCO₂ probably attains very high values of 48mm/Hg, as observed by the past researchers, and due to it'sinstantaneous diffusion even through tissue planes, it may equilibrateeasily with the PCO₂ of the traversing umbilical vein making it higherthan the previously equilibrated lower levels after an exchange with thematernal blood at the intervillous space. Because of it's volatility andhigh diffusion coefficient, the CO₂ diffusion from

TABLE 5 The artery/vein PO₂ (mm/Hg) PCO₂ (mm/Hg) Author Uterine artery95 32 Longo (1972) Uterine vein 40 40 Longo (1972) Intervillous space(IVS) 30-35 38 PO₂ (Pritchard et al) Umbilical artery 15 48 Longo (1972)Umbilical vein 27 43 Longo (1972) (note the PCO₂ of 43 of umbilicalvein, much higher than 38 of the IVS) Non pregnant controls - Systemic(venous blood) 40 45 Guyton AC Interstitial fluid 40 45 Guyton AC Lungalveoli 104 40 Guyton AC Pulmonary 104 40 Guyton AC . (oxygenated blood). (after equilibrating with alveolar air, and before the entry ofbronchial venous blood)the AF into the cord blood can be instantaneous. The AF water diffusionis 50 ml/hour into the cord blood, during the mid/late pregnancy(Plentil 1961). It is significant to note that the diffusion capacity ofCO₂ across the alveolar membrane, for long had not been measured, as thediffusion is instantaneous, and the difference across beingimmeasurable.

Studies of acid base status of amniotic fluid (AF) was published byRooth, Sjostedt, and Caligara (1961). They concluded that the pH and theCO₂ tension in the AF reflect corresponding values of the umbilicalartery (in the range of 45-60 mm/Hg), and those of the fetalsubcutaneous tissues, and that towards the end of pregnancy there issignificant increase in the carbon dioxide tension of AF from 51 to 58mm/Hg. Lower numbers were indicated in their later studies, though theexact numbers were not specified. It is questionable whether theseobservations of AF are the cause or effect of what are reflected in theumbilical artery, and in the fetal subcutaneous tissues. It is mostplausible they are the cause. Except for fetal urine, there is no fetalcontribution to the AF later in pregnancy, and it's chemistry and volumeare mainly a result of exchange with the maternal extracellular fluid,the AF being replaced every 3 hours. Accordingly, if the umbilicalartery and the fetal subcutaneous tissues show similar pH and PCO₂values as those of AF, it is due to the rapid diffusion of CO₂ from theAF into the fetal tissues and the umbilical cord, proportionally raisingthe values both in the umbilical artery and the vein. Even if the normalfetus generates more of CO₂, there is no physiological means of how itis reflected in the AF, except through fetal urine that CO₂ is not aconstituent of. Hence it is most plausible that the CO₂ from the AF hasdiffused incessantly into the umbilical cord, and also into the fetalsubcutaneous tissues, it's original source being the uterine myometriumitself that surrounds the whole of the non-placental amnion.

It was previously discussed that the AF content of CO₂ can be very high,especially in oligiohydromnios. It is highly critical to explore how theCO₂ of the AF has attained such high value despite the low maternal PCO₂of 40 mm/Hg in the uterine vein (45 in non-pregnant controls), and 32mm/Hg in the uterine artery (lower than non-pregnant value of 40) and 38mm/Hg in the placental intervillous space. The explanation can be asfollows—The CO₂ is mainly the product of carbohydrate metabolism,especially of the citric acid cycle. The citric acid cycle is deemed tobe very active in rapidly enlarging uterus all through pregnancy. Thoughthe essential amino acids needed for protein synthesis are required tobe supplied from the maternal diet, most of the non-essential aminoacids can be synthesized by the mother from carbohydrate sources.Alanine and hydroxyproline are synthesized from pyruvate; glutamate andglutamine that make up the largest amino acid pool of the body areintimately associated with, and are synthesized from α-ketoglutarateduring transamination of α-ketoglutarate. Aspertate and aspergine areformed from oxaloacetate; serine is derived from 3-phosphoglycerate; andglycine formed from glyoxalate. The uterus enlarges 16 times in weightat term from it's non-pregnant state. This is mostly through hypertrophy(enlargement of the diameter/length of individual muscle fiber), andvery less through hyperplasia (increase in the number of muscle fibers).There is great expansion of sarcoplasm of the enlarged muscle cells thatstore ATP, glycogen (synthesis of which needs significant number ofATP), and creatine phosphate that also stores ATP in an alternate formin the muscle. When proteins are synthesized, large portions of ATP arealso used to form the peptide linkages that store energy in thelinkages. These indicate that there must be very actively ongoing citricacid cycle in the uterine musculature for the generation of needed aminoacids, and the needed ATP. There is evidence that there is enormousproliferation of mitochondria in each cell, for needed ATP production,and for ongoing glucose combustion. In a virtual uterine proteinanabolic process, just as the lipid anabolic process of lipogenesis, thecarbohydrate catabolic process is intertwined. It increases the CO₂generated by exponential amounts in the proliferating uterinemusculature/decidua that can immediately diffuse into the adjacent AF.As the diffusion of the gas is directly proportional to the diameter ofthe space it diffuses into, it will be more into the amniotic cavity(with very high transverse and longitudinal diameter) rather than theuterine venous capillaries. This localized rise of CO₂ in the enlarginguterine interstitium can happen, despite the low CO₂ tension elsewherein the maternal body. The amniotic cavity being a low resistant highvolume chamber, and the solubility coefficient of CO₂ being very high(that is, CO₂ is physically and chemically attracted to the watermolecule), the CO₂ diffusion that is instantaneous through any of thetissue planes (including the amnion), can be significant towards the AF,than into the uterine venous circulation.

(As an alternative, dissociation of urea [NH₂—CO—NH₂] of the AF to CO₂can be thought of, though it will raise toxic ammonia levels of AF whichthe fetus has to swallow. The fetal liver is capable of handling ammoniaagain entering through the gut, by reformation of urea. However, thebiochemical support for urea dissociation (into ammonia) after it isformed is not found. Despite long standing uremia in an end stage renaldisease, only blood urates, hippurates, indoles, benzoates, phenols, andpolyamines are normally found to be elevated, but not the ammonia.)

It may be noted that the uterine vein PCO₂ is 40 mm/Hg, whereas it isonly 38 mm/Hg in the placental intervillous space (most probably theequilibrated value, such equilibration being instantaneous for CO₂). Itindicates that there is definite higher non-placental myometrialcontribution of CO₂ to the uterine vein which implies that myometrialinterstitial PCO₂ must be greater than 40 mm/Hg to start with, thatlater equilibrated to 40 mm/Hg, joining with the intervillous blood asit drains into the uterine vein. Such PCO₂ greater than 40 mm/Hg in themyometrial interstitium is almost reaching non-pregnant values. Inessence, the myometrial production of CO₂ is far greater than the fetal,despite a predominant carbohydrate metabolism in the latter.

The ultramicroscopic structure of the amnion demonstrates that there aresignificant intracellular and complex intercellular canalicular systemall through the layers that transmit fluid from the maternalinterstitial compartment to the amniotic cavity. However, there isselectivity, as AF does not truly represent all the constituents ofmaternal interstitial fluid. Yet the respiratory gases of interestfollow the laws of gaseous diffusion in the same manner: (1) in agaseous mixture, (2) as dissolved gases in a solution, or (3) whenchanging from gaseous phase into a dissolved state in liquids.Paradoxically, the cell membrane is even less restrictive than theliquid barrier for the passage of the respiratory gases (Guyton A C).

And due to the avascular nature of the amnion, the PCO₂ of theinterstitial fluid, and not the arterial capillary end, is relied on. Itcan be stated that through the traversing transcellular andintercellular canalicular system of the amnion, there is a continuum ofthe uterine interstitial fluid, of which the respiratory gases are partof. And if there is an occasional cell membrane intervening, it poses nobather to either O₂ or CO₂. The following laws of net gaseous diffusioninto a chamber (Guyton A C) are herein applicable. The amniotic cavityin this instance can be considered as a closed fluid chamber amenable tosimilar laws of gaseous diffusion—

1. Greater the pressure difference (P₁−P₂) across, greater will be thediffusion (Henry's law of solubility coefficient of gases), that is, thediffusion is from higher to lower pressure, P₁ and P₂ being the involvedhigher and lower pressures respectively.2. Greater the solubility of a gas (S), greater will be the diffusion(Henry's law of solubility coefficient of gas).3. Greater the cross-sectional area (A) of the chamber of diffusion,greater is the diffusion.4. Greater the molecular weight of the gas (MW), lesser will be thediffusion, that is, the rate of diffusion is inversely proportional tothe square root of it's molecular weight (Graham's law of gaseousdiffusion).

-   -   The rate of gaseous diffusion (D) across a fluid compartment can        be shown as below—

$D \propto \frac{( {{P\; 1} - {P\; 2}} ) \times A \times S}{\sqrt{MW}}$

Based on the above laws of gaseous diffusion, the net diffusion of CO₂is 20 times that of O₂, because of it's very high solubility coefficient(S) that makes a gas to be chemically and physically more attracted toit's solvent, in this case, the water molecule. Accordingly, it is not asurprise, nor it is unexplainable, if the AF content of CO₂ has beenfound to be very high.

The uterine myometrium being the source of the high AF CO₂ content isfurther supported by the fact that in IUGR, the AF was found to containexceedingly high amounts of CO₂ (as was documented by Nicolaides et al,1989), but as per the foregoing biochemical discussion in the previoussections, it is very obvious that in IUGR, the fetus is deprived of bothglucose and O₂, the invariable elements needed for CO₂ production, andanaerobic glycolysis generates no CO₂. Hence the source of AF CO₂ can beonly the myometrium, and never an IUGR fetus, though fetal oliguria canconcentrate it within the AF (see the section ‘Fetal oliguria andoligohydromnios’).

The Possible Oxygen Diffusion into the AF

The above deduction undoubtedly proves the possible high CO₂ diffusionfrom maternal extracellular spaces into AF. As it's rise in the AF isnot subtle, due to it's high solubility/high diffusion coefficient, andwas well documented, though the source was not explored being implied asfetal (Gadd R L, 1970; and Nicolaides et al, 1989), it neverthelessgives room to contemplate such possibility with oxygen diffusion also,though not with the same ease or of proportion. It was already mentionedthat the interstitial fluid PO₂ can approach a maximum of 95 mm/Hg, ifthere is significant increase in the rate of blood flow, and of themetabolic activity of the organ (Guyton A C), and both are inevitableduring pregnancy. The blood flow is augmented in exceeding proportionsbecause of the shunt effect of the placenta that decreases theperipheral resistance markedly in the uterine artery and it'stributaries supplying the whole of the uterus. It follows that the PO₂of the interstitial compartment of pregnant uterus can be higher than 40mm/Hg (the value of interstitial PO₂ elsewhere), and it is evidentlymuch higher than the PO₂ of the placental sinusoids. Though historicallythe amnion overlying the placenta is considered as the significantcontributor to the volume and to the contents of the AF, as far asoxygen diffusion is concerned, the non-placental uterine area conformsto a source of higher oxygen diffusion secondary to higher PO₂, and as aresult higher net diffusion gradient into the non-placental interstitialuterine compartment, and then into the AF (further aided by the benefitof the in-vicinity placental shunt effect that actually pulls the bloodfrom the uterine artery, and the systemic circulation).

Based on the Above Formula of the Rate of Net Diffusion of a Gas, theFollowing Observations for the diffusion of O₂ into AF can be made—1. The PO₂ of the uterine interstitial fluid can be higher duringpregnancy, in areas surrounding the non-placental amnion. This is incontrast to the low oxygen pressure in the AF itself. This will increasethe net diffusion, due to increased pressure gradient of oxygen (P₁−P₂)across the amnion channels. The selectivity of the amnion may not beapplicable to the gases of biological interest, and to the laws ofgaseous diffusion universally governing the kinetics of gaseousdiffusion, either through solids or fluids, and either into gaseous orfluid compartments/chambers.2. The cross-sectional area (A) of the amniotic cavity (eitherlongitudinal or transverse), configured as a chamber, is also very high,thus increasing the rate of diffusion of O₂.3. The molecular weight (MV) of O₂ is low (32). This is inverselyproportional to the rate of diffusion. With regard to free molecules notattached to others (O₂ is free molecule; in CO₂, it is physicallyattached to carbon), linear movement at high velocity is possible(Guyton A C).4. With regard to the distance of the gas to be traveled, in thiscontext, the area of importance is the AF very adjacent to the uterinewall itself where the fetal face and the oral area are located, and thefetal swallowing is effectuated. It is the narrower and the highlyvascular lower uterine segment in the cephalic presentation. Hence, thedistance needed to travel by the molecular oxygen is very less.Obviously, as the oxygen travels towards the center of the amnioticcavity, it's effective AF concentration probably diminishes due to thefactor of dilution. Even after engagement, until the descent duringlabor when it touches the pelvic floor, deflexed attitude of the fetalhead is prevalent which makes it's facial approximation with the uterinewall more feasible. This causes the fetal swallowing of AF with higherO₂ content, before the gas is diffused.

Even after the descent and flexion of the fetal head, in the commonlyprevailing left occipito-anterior position, due to the high concavity ofthe sacrum and the similar curvature the uterus tends to maintain belowthe pelvic inlet during labor, the fetal oral area will be still facingthe concavity of the posterior wall of the pelvic cavity below theoverhanging promontory of the sacrum, making the fetus swallow the AFvery close to the uterine wall. It can be further said that the neonatalrooting reflex (so strongly prevalent in the neonates, and is most basicfor their instinctive acts meant for cooperatively seeking the maternalbreast, suckling, swallowing, and survival) was sufficiently rehearsedby the fetus in-utero, making it reflexively turn it's head towards thatside, whenever the uterine wall/AF motion touches it's either cheek (bymaternal position or movement). This helps the mechanism of fetalswallowing taking advantage of the uterine disposition that is closestto it's cephalic orientation, even in complete head-flexed attitude. Itobviously facilitates the fetus swallow more of oxygen and the solutesof AF that are the products of diffusion through the amnion, and in thesame token, less of it's own urine excreted at the opposite uterine polewill be swallowed, as more of it will be exchanged with maternalcirculation before equilibrated with the AF of the cephalic pole. The IVhypertonic or the transamnionic isotonic glucose supplements, apart fromimproving fetal strength for swallowing, will also enhance the sweetnessof the AF, making the fetal swallowing more voluntary. The normal newborn behavior as observed by past researchers is a testament to all theabove statements. The awake and a hungry newborn exhibits rapidsearching movements responding to tactile stimuli, as far away as thesides of the jaw and the head (Brazelton 1986). The new born also hasfine appreciation of taste, exhibiting preferential suckling response(with overall less pauses) when fed with different concentrations ofsugar solutions, and great resistance to saline feeds (Johnson &Salisbury, 1975), more of such experiences increasing the complexity ofthe responses.

What Makes the Oxygen Diffusion Across the Cells of the Amnion, and theInterstitial Fluid that Permeates it's Canalicular System a Possibility—

From the intervillous space, to reach the fetal hemoglobin, oxygen hasto traverse the following barriers before being bound to the fetalhemoglobin—

1. Maternal plasma, 2. Syncytiotrophoblast, 3. Cytotrophoblast, 4. Acompact villous stroma made of fibroblasts, delicate collagen fibers,and Hofbauer cells, 5. Fetal capillary wall made of fully matureendothelial cells, and 6. Fetal plasma.

It means to say that before oxygen enters fetal hemoglobin, it traversesthrough maternal and fetal plasma interstitial fluid, and in addition,few cellular compartments. Similarly, oxygen can effectively traversethe membranous barrier of the amnion.

It is worthy of note that AF amino acid concentration is same as that ofmaternal plasma (R. Lisle Gadd), whereas glucose is present in lowerconcentration. The proteins are also lower. It is obvious that the aminoacids have diffused into the AF from the uterine myometrium. Due toenormous growth and enlargement of the uterus to 10-20 times it'snon-pregnant size, there has to be high amino acid turn over in theorgan. Such high amino acid turn over, and the increased concentrationas a result, are deemed to be reflected in the uterine interstitialfluid, and in turn in the AF (most probably by transit throughintracellular and complex intercellular canalicular system of theamnion, as a cell pore size is much smaller than the molecular size ofany amino acid). It is similar to the high trafficking of a rawmaterial, needed for a local manufacture. The increased demand/metabolicrate/turn-over of a substance in conjunction with increased vascularityof an organ, can accelerate it's diffusion into the organ. Similareffect can be observed with respect to oxygen diffusion into themyometrium, also subject to similar setting, as oxygen is also a neededraw material for the profoundly increased mitochondrial citric acidcycle in each of the myometrial cells, saving ATP and glycogen. It wasadequately stressed that cell/fluid bathers are deemed to beinsignificant for oxygen diffusion and therefore it's simple diffusionshould far surpass the amino acid transit via the amnion. The diffusionof O₂ should be more efficient also for the reason that the oxygenhaving lower molecular weight than the amino acids, yet has to encompasssmaller span of distance to exert it's desired effect over the fetus,and AF collection for measuring amino acid levels must have beenrandomly drawn, not necessarily from the AF adjacent to the uterinewall, and their levels are still equal to the maternal interstitialfluid.

The above matter of oxygen diffusion sufficiently into the AF isscientifically grounded, based on:

1. The standard laws of gaseous diffusion (as elaborately outlinedearlier in this discussion favoring oxygen diffusion) across cellmembranes and body cavities.2. The presently available knowledge of the gaseous exchange at the lungand tissue capillary level based on the partial pressures of concernedgases, and their operative net diffusion gradient (the partial pressureand diffusion gradient of O₂ during pregnancy deemed higher innon-placental myometrium/decidua).3. The proved high CO₂ content of AF by many past researchers (that wasbased on laws of gaseous diffusion and exchange of biological gases, asstated in 1 and 2 above).4. The AF amino acid content approximating that of maternalextracellular fluid, so reflected due it's high turn-over in theadjacent uterine interstitium during pregnancy. Similar higher turn overin the myometrium is expected of oxygen also, with the laws of diffusionin fact favoring better oxygen diffusion than that of the amino acids.5. The high PO₂ of non-placental uterine interstitium further enhancedby the in-vicinity placental shunt effect.

It can be concluded that the maternal D-glucose supplements willincrease the AF glucose content (also relieving the existingoligohydromnios, in a similar manner polyhydromnios is observed inmaternal DM), and the improved volume as well as the palatability willheighten fetal swallowing of AF that contains more of glucose withsufficient amounts of oxygen also for it's aerobic oxidation (theintravenous hypertonic D-glucose therapy that is initially implementedcan also supply needed ATP and the energy needed for swallowing, even ina previously moribund fetus). The isotonic D-glucose transamnioticsupplements have similar direct effects.

The Biochemical Aspects of the Maternal Carbohydrate Metabolism

It has been generally assumed that carbohydrate tolerance is impaired inpregnancy, and thus pregnancy constitutes a diabetogenic stress to themother. The fact that diabetes is first manifest during pregnancy, andthat the diabetic women frequently require increasing amounts of insulinas pregnancy advances, and the occurrence of glycosuria duringpregnancy—are all cited as evidence to support this view. It is possiblethat it could be present earlier but uncovered during pregnancy, as itis a milestone event in time, and it is common rather than an exceptionthat the mother as a whole is deservingly put under a microscope, makingthe statistical incidence of diabetes seem more than it's actualnumbers.

However, interestingly, the normal fasting or post prandial/post glucosechallenge blood sugar shows very close parallelism (in it's values andfluctuations) with the non-pregnant controls during pregnancy, in markedcontrast to levels or patterns prevalent in diabetes itself.

Insulin Resistance

Pregnancy is characterized by major physiological adjustments affectingevery system of the body. The changes are frequently in a scaleotherwise unseen in healthy non-pregnant controls, and can belegitimately subject to diagnostic concern and confusion. Such majorchange and a matter of great concern is the normally disproportionatelyelevated maternal serum insulin levels in the face of perfectlymaintained blood glucose levels (in fact at a slightly lower level thanthe non-pregnant controls). Many other maternal serum values of clinicalsignificance also show deviations that have to be interpreted withdiscretion.

There is reason for believing that many of the maternal changes arepurposeful and mostly harmless, being directed to the welfare of thefetus. The fetal status in pregnancy is no doubt physiologicallyexalted, as obviously it is the only way that the theme of pregnancy canbe accomplished. ‘The fetus thrives at the expense of the mother’ can beclinically evidenced by the fact that even when the mother is profoundlyanemic due to iron deficiency, her fetus has grown well, and is rarelyanemic. The author inventor had seen many such cases where the mothers'tongues were papery pale with their hearts pounding in hyperdynamiccirculation, that gave room for concern how they ever survivedpregnancy, but the delivered fetuses were pink to their extremities, asevidently the placenta concentrated iron very efficiently. It can seemas though the placenta worked solely and faithfully for the fetus, andconspired against the mother.

The insulin peak and the insulin antagonists—Blood insulin levels risethrough pregnancy both in fasting state, and after glucose load. Theinsulin peak is especially dramatic late in pregnancy (from 125 μU ofearly pregnancy, it can rise in mid pregnancy to 175 μU, and it can be340 μU in late pregnancy) (Spellacy W N et al, 1963 and 1965). Thisparadox of increased amount of circulating insulin while normal glucoselevels are prevailing in the pregnant organism, is due to the presenceof anti-insulin factors like glucocorticoids, estrogen, and theprogesterone, but the most important insulin antagonist, as specifiedearlier, is the HPL, a polypeptide produced by the syncytiotrophoblastof the placenta. HPL produced by the placenta is only present in thematernal blood, but not in the fetus. Other possible culpritscontemplated by past researchers are—(1) increased levels of xanthurenicacid—it is an accumulated tryptophan metabolite that can bind to insulindecreasing it's biologic activity, when the normal metabolic pathways oftryptophan are altered due to pyridoxine deficiency, usually prevalentin pregnancy (Zartman E R et al, and Spellacy W N. et al, 1972); (2)decreased chromium levels in pregnancy—chromium couples with insulin andmay potentiate it's metabolic activity in the peripheral tissues(Davidson I W F, Burt R L, 1973); (3) Freinkel et al (1958) and Posner BI et al (1974) proposed that placenta destroys insulin with at least twosoluble insulinase enzymes, and thereby there is need for more of it'sproduction.

But the possible role of exponentially elevated maternal FFA levels, andthe events encompassing it, and others, in causing maternalhyperinsulinemia, as contemplated in this writing by the authorinventor, is discussed in the subsequent paragraphs.

HPL—HPL produced in enormous quantities in the placenta has greatphysiological significance during pregnancy. It causes increase of FFAcontent in the maternal circulation by mobilizing the lipid stores, andin this respect seems to be more dominant than insulin, because insulinis anti-lipolytic. Once there is increased FFA, the maternal tissuesutilize more of it (in the adult human the FFA is the first fuel to becatabolically used) sparing glucose to be diverted to fetoplacentalcirculation which is a slower process, because the amount of glucosespared from all tissues of maternal body is much more and generalized,compared to the substantially lower amounts of glucose getting into thefetus only through the narrow channel of the umbilical cord (thus thematernal body intended to be acting as a glucose reservoir, for thesustained glucose supply to the fetus). As long as there is persistentnormoglycemic levels of circulating glucose, it is expected to releaseinsulin from maternal pancreas. However, the HPL, apart from mobilizingFFA from fat stores, also prevents insulin's effects on the cellmembrane ‘carrier transporters’ of glucose in the maternal tissues,while the released free fatty acids further compete with glucose fortheir own utilization by the maternal tissues.

The maternal pancreatic response—The maternal pancreas is onlyconditioned to produce insulin as glycemic response, but does notperceive that insulin and also glucose are not being effectively used bythe maternal tissues, except the placenta, and the fat depots. However,this fundamental homeostatic control though somewhat distorted duringpregnancy is still not ineffective, because the rise of insulinproportional to glucose level (indeed a disproportionately high insulinrise) is needed to enable facilitated diffusion at the utero-placentalinterface, and to build maternal fat depots from early on, and is veryrelevant to enact the theme of pregnancy.

The lack of placental resistance to insulin even in diabeticpregnancy—As explained before, the placental tissues are deemed to besensitive to insulin action even in diabetic pregnancy, as evidenced byfetal macrosomia, despite the maternal insulin resistance. Marshall R Net al and Posner B I et al in 1974 demonstrated that the placentalbinding protein of insulin is similar in molecular weight and infunction to the insulin receptor protein found on the cell membrane ofthe maternal fat and the liver cells, that are also unaffected by thesubject's insulin resistance, as obesity in diabetes is common ratherthan an exception.

The Stimulus for Maternal Lipogenesis—

(1) Insulin—Insulin normally is lipogenic. Hence, insulin rise is alsoimportant for the needed maternal fat deposition. It was previouslymentioned that Vallence-Owen in 1965 had suggested that during insulinresistance as in diabetes, there is impaired uptake of glucose by themuscle, but not by the adipose tissues. It seems to be true also inpregnancy, as the essential fat deposition is not impaired, as would beexpected of maternal insulin resistance. Such mechanism of fatdeposition is obvious even in pre-diabetes, as in these patients, morethe insulin resistance, more can be the manifest obesity.(2) The biochemical factors—Biochemically, it is obvious that thoughhormone sensitive lipoprotein lipase (that is responsible for lipolysis)inhibition by insulin is impaired, the insulin's action on lipogenicenzymes like acetyl-CoA carboxylase, ATP-citrtae lyase, and fatty acidsynthase has not seemed to be similarly undermined. This makes possiblein the maternal tissues for both lipogenesis and lipolysis to besimultaneously ongoing, but at a different degree during differenttimes. The maternal lipogenesis is dominant when the fetal FFA demandsare less, almost showing a linear progression up to 25^(th) week, whenthe curve gets plateaued until term. The mother seems to de-esterifythese fat depot stores later on during pregnancy when the circulatingFFA levels are found to be maximum during 37-40 weeks. It correlateswith peak fetal lipogenesis, when the fetus can incorporate at this timethe maternally derived FFA. In response to the same amount ofhyperinsulinemia, the maternal lipid metabolic response during eachtrimester of pregnancy had proved to be different. In the secondtrimester as during the post-partum, the insulin's inhibitory effect onlipolysis seems to be 51% of non-pregnant controls, whereas in the thirdtrimester it seems to be only 30% (Sivan et al, 1999) making maternallipolysis maximally manifest during this period, for rapid fetal fataccretion incorporating the maternally derived FFA.(3) Hormonal effects, increased food intake, and decreased physicalactivity—estrogen rise during pregnancy also seems to play a veryimportant role in fat deposition, as it is very obvious that this sexhormone is what sets apart the sexual characters of the female body(apart from absence of androgens), and the same fat distribution can beevident in men castrated before puberty. It is obviously an evolutionaryaccomplishment of the races so as the females, needed for multiplicationof the species, are not to be expendable biologically as a result ofintermittent food shortage (NB. Myant). The presence of progesteroneduring pregnancy shall have added effect to lipogenesis acting at thehypothalamic level (F. E. Hytten). Improvising and additive to theincreased food intake, the physical activity of the pregnant woman islowered, with the metabolic rate set at a lower gear, mostly due to thethyroid hormone during pregnancy being bound, and inactivated. Bothfactors contribute to conservation of energy leading to maternal fatdeposition starting very early on (F. E. Hytten).

The Author's Theory to Account for the Manifest MaternalHyperinsulinemia During Normal Pregnancy—

1. The role of the circulating FFA of the maternal blood in causingmaternal insulin resistance and hyperinsulinemia—

-   -   (a) The very high insulin levels per deciliter of blood in        pregnancy when blood sugar per deciliter is normal, being        steadily consistent with non-pregnant controls throughout        gestation, give the impression that the insulin peak is a        deliberate overshoot, being manifestly exaggerated, despite the        allowance given to all anti-insulin factors deemed to operate        during pregnancy. It must be purposeful, as insulin levels and        effects during pregnancy are not only related to glucose        homeostasis, but also seem to be related to lipid homeostasis.        Unusually high lipogenesis needed for building maternal fat        depots is primarily induced by enzyme-stimulating action of        insulin. Such insulin elevation is effectuated because glucose        is not the only insulin stimulant. Increased level of FFA in the        blood is also an insulin stimulant, such FFA increase as already        stated, being primarily induced by the action of HPL. However,        in this situation, the presence of both glucose and elevated FFA        levels of blood are needed for the pancreatic insulin release        (G. Grodsky). Such combination is accomplished, and prevails all        through pregnancy, as glucose levels are maintained as well by        HPL antagonizing maternal glucose utilization in the muscle. The        FFA levels are remarkably high in pregnancy that reaches a        maximum in the later part that also correlates with the towering        peak of insulin surge at this time. At 37-40 weeks of gestation,        the FFA levels are 1226 μEq/L (768 μEq/L in the non-pregnant        controls), a 60% increase (Burt, 1960). Insulin peak during late        pregnancy is 340 μU/dl, whereas it is only 125 μU/dl during        early pregnancy (Spellacy W N et al, 1965) as earlier mentioned.        Such dramatic increase of FFA can create an obese adipocyte, in        the setting of rapid onset hormone regulated maternal        lipogenesis.    -   (b) In the adult human the FFA is the first fuel to be        catabolically used, thus sparing glucose oxidation, and in that        manner, the elevated FFA can block the effects of insulin in the        insulin-sensitive peripheral tissues, especially the muscle        (Mayes P A, Regulation of carbohydrate & Lipid Metabolism, page        263: Text book of Harper's Review of Biochemistry′, 19^(th)        edition). Consequently, it triggers a cascade of events, such as        hyperinsulinemia and the insulin receptor down-regulation. When        pronounced, it can set up a stage for gestational diabetes.

The maternal insulin peak seems to be the summative effect ofanti-insulin factors (that are classically attributed to causinghyperinsulinemia), and also due to elevated FFA levels, as the insulinpeak mirrors more of the heightened FFA levels late in pregnancy, thanthe steady state of blood glucose levels throughout. It is not tooverlook the fact that insulin peak also correlates with glucose peakthat is not as dramatic as FFA peak, and that without insulin resistanceon glucose homeostasis, such insulin peak would have resulted maternalhypoglycemia.

In the second trimester as during the post-partum, the insulin'sinhibitory effect on lipolysis seems to be 51% of non-pregnant controls,whereas in the third trimester it seems to be only 30% (Sivan et al,1999) making maternal lipolysis maximally manifest during this period,for rapid fetal fat accretion. The lipolysis of third trimester is dueto (many of) anti-insulin hormonal effects, that rise the FFA levels tothe peak, which in turn can rise insulin levels, as insulin's inhibitionon lipolysis is blunted, but not the stimulatory effect of FFA levels oninsulin secretion (in a manner similar to glucose-insulin homeostasis,that insulin gets secreted as glycemic effect, while glucose itself isinsensitive to it's effect).

2. The maternal fat deposition in causing maternal insulin resistanceand hyperinsulinemia—

The maternal lipogenesis shows a linear progression from very early on,up to 25^(th) week, when the curve gets plateaued until term. The fatdeposition during pregnancy is mostly central, a state that resemblesnon-pregnant central (trunkal) obesity, and it can be speculated thatthe fat deposition (central obesity) acquired in pregnancy in such shortterm (due to many factors as seen in the preceding subsection of‘stimulus for maternal fat deposition’) and at such rapid pace can alsobe accompanied by it's associated pervasive features ofinsulin-resistance and hyperinsulinemia, just as seen in non-pregnantobesity, mainly triggered by the obese-adipocyte, that is typically seenin central obesity. In non-pregnant central obesity, the molecular linkbetween obesity and insulin resistance/effect seen in tissues such asliver, muscle, and in the fat tissue (Jeffrey S. Flier et al) can beexplained as due to: FFA that are increased, and capable of impairinginsulin action on glucose receptor sites; resultant hyperinsulinemiaitself that can induce cell membrane insulin-receptor down-regulation;intracellular lipid accumulation in the adipoctyes, creating an‘obese-adipocyte’, obesity generally being caused more by increasing incell size rather than in the number of the adipocytes; various peptidesincluding cytokines produced typically by obese-adipocytes are capableof modifying insulin action, an obese adipocyte being not only a lipidstorage unit, but also an active endocrine cell that releases numerousagents in a regulated fashion. A factor called ‘resistin’ secreted byadipocytes can increase insulin resistance in this setting.

In essence, the exceedingly high circulating FFA, the rapid-onsetmaternal fat deposition, and the obese adipocyte, all associated withpregnancy can combindly exert powerful inhibitory effect on normalinsulin action, and can explain the inordinately high insulin peak. Suchmechanism of fat deposition and obesity being also obvious inpre-diabetes, and the fact that weight reduction even of modest naturecan increase insulin sensitivity—are the testaments to what is likelyinduced by obesity and obese-adipocytes, as stated above. The recentlyevolved concept of metabolic syndrome, has central (abdominal) obesity,hyperlipidemia, and insulin resistance as three of the five features init's constellation of associated metabolic disturbances.

3. Other maternal contributing factors—The essential amino acid arginineis an insulin secretagogue, whose action can be preserved even whenglucose stimulated insulin secretion is impaired (Powers A C).

It can also be understood now that the maternal adjustments, as can bededuced from the scope of the discussion, are the result of an alreadyover stretched adaptation even during normal pregnancy, being so manyoperational devices put together to divert the circulating glucose tothe fetus, which can not be enabled any more during fetal IUGR ofplacental insufficiency. Maternal IV glucose supplement is similar to,but accomplished by easier means than what the maternal devices inpregnancy are trying hard to achieve. Glucose tolerance curves after IVglucose load show slightly lower values in all stages of healthygestation, compared to the non-pregnant controls. Inferentially, thereis evidence basis to believe that IV glucose supplements are welltolerated during pregnancy than in non-pregnant state which provides asound basis for effectuating such clinical contemplation, howeverwithout overlooking the fact that insulin resistance is inherent to thepregnant state, and is inevitable.

How the Induced Therapeutic Maternal Hyperglycemia is Different fromDiabetic State—1. In the setting of fetal IUGR, following the therapeutically inducedmaternal hyperglycemia with IV D-glucose, the induced hyperglycemic peakis transient, and is of very short duration, with a maximum of an hour,mostly simulating an IV glucose challenge test, or the postprondial peakafter a heavy meal, whereas in uncontrolled diabetes the hyperglycemicpeak is persistent.2. In diabetes, fetal hyperglycemia has resulted, whereas following thetherapeutic maternal hyperglycemia induced in an IUGR pregnancy, thefetal hypoglycemia is corrected.3. There is accompanying maternal ketosis in uncontrolled diabetes thatis responsible for fetal anomalies, if such ketosis is significantduring the first trimester, but ketosis is not part of the clinicalpicture in therapeutic maternal hyperglycemia.

Accurate Diagnosis of Fetal IUGR by History, and by PreliminaryDiagnostics

Conventionally, the obstetric follow up of normal as well as at-riskpregnancy is monitored by bed side evaluation of the fetus/mother, andalso by the diagnostic ultrasound evaluation. Before doing either, anaccurate determination of gestational age is important on which thediagnosis of IUGR is contemplated and pursued. To accomplish that,complete and reliable history taking is paramount, and time spent onthis is time worth spent.

History—As an IUGR fetus is initially suspected based on a reliable dateof LMP (last menstrual period), a careful and detailed menstrual historyis important. The combination of both reliable dates, but wronglycalculated gestational age happens in patients with oligomenorrhea withinfrequent periods, for example every two months cycles. Theobstetrician after noting a reliable calendar noted LMP, if forgets tonote the patient's usual duration of cycles as two months, there will bea month incorrectly accounted for, in the calculated gestational age. Ifthe patient's LMP was March 1, and if she comes on September 13, with nodetailed menstrual history elicited, based on a calendar noted reliableLMP of March 1, her gestational age can be calculated as 28 weeks, whenin fact her actual pregnancy duration is 23 weeks and 2 days. Thepregnancy-wheel being based on the standard menstrual cycle of 28 daysis the reason that the physician will come up with the gestational ageof 28 weeks. In these patients, to calculate the correct gestationalage, adjustment of days should be done based on ovulation timing, whichis always 14 days before the first day of the next expected menstrualperiod (the missed period in the event of pregnancy), whatever be thelength of the cycle. It is because the life of the corpus luteum is 14days, unless the event of conception dictates otherwise, to prolong it'scontinued function of progestational support until the placentacompletely takes over. It is a common understanding that ovulationoccurs 14 days after the first day of a typical 28 day cycle. To beprecise and all-inclusive—ovulation occurs 14 days before the first dayof the next menstrual period, or 14 days before the date of the missedperiod (in the event of conception) of any type of cycle.

A simple and confident way to always calculate gestational agecorrectly—from a properly elicited menstrual history, note the date ofthe missed period (that is, if the cycle is of regular duration, though,the period is lengthened), and count back 28 days (exactly 4 weeks), andtake that date as the LMP for calculation purposes (can be called CLMP,the corrected LMP, or LMP for calculations). From this date thecorrected gestational age, and the corrected expected date of delivery(EDD) can be calculated from the wheel. In the exemplified patient withregular 2 months cycles and March 1, as LMP (the real LMP, and can becalled RLMP), her date of missed period is May 1. Counting back 28 days,her CLMP is April 3, from which the EDD is calculated using pregnancywheel. With this type of calculation the physician never has to worry ordoubt his or her numbers in the rush of the out-patient clinic,emergency room, or after a night-call. The ‘Corrected Last MenstrualPeriod’ (CLMP) calculation can be stated as follows—‘With regularmenstrual cycles but atypical cycle duration, count back 28 days fromthe date of the missed period to get the date of corrected LMP, foraccurate calculation of the gestational age.’-Sumathi Paturu's rule forcorrected LMP.

Or it can be simply said ‘Count back 28 days from the date of the missedperiod to get the corrected LMP’

The correct estimation of gestational age can be similarly done if thecycle is shortened, as a 21 day cycle, when the actual gestational ageis 1 week more (if calculated correctly), which has practicalimplications in deciding interventions needed in a post-term pregnancy.If not correctly calculated, a decision can be made to deliver at 41weeks or after, mistakenly calculated as 40 weeks or after. In thissituation, if a patient's RLMP is July 1, and if she has regular 21 daycycles, her missed date is July 22, and counting back 28 days, the CLMPis June 24, from which the correct Expected Date of Confinement (EDC) orEDD is calculated.

A detailed menstrual history should include the duration of menstrualflow also, as after conception, some women can have spotting or 1-2 daysbleeding that corresponds to the time of their cycles, which can bemistaken for regular periods by the patient, until such atypicalbleeding ceases. In this instance the actual length of gestation islonger than what the patient reports as. U/S (ultrasound) confirmationis helpful, and it can be found to correlate with the typical LMP (aselicited by detailed menstrual history) being earlier than the reportedLMP.

Different clinicians use different ways of calculating the correctgestational age when the cycle length is atypical, by adding orsubtracting concerned number of days from the date of LMP or EDC. Sometimes, one may need a calendar to quickly and confidently correct thedays, but the herein specified manner of calculating can be founduseful, as it is quicker, can be done with out calendar, and notconfusing. Above all, it is a better means to communicate in anobjective and understandable terms, as there is a similar mode ofcalculation whether the cycle is shorter or longer than the typical 28days menstrual cycle. Just as the configuration of the pregnancy-wheelused in the clinics, the Näegele's rule calculation also ispresumptively based on the typical 28 day menstrual cycle, with thepregnancy duration of 10 lunar months (a lunar month comprises 28 days),that is 280 days, counted from the first day of LMP.

With the corrected LMP (CLMP) date configured in the manner as specifiedabove, one can use the ‘pregnancy-wheel’ or the Nägele's rule tocalculate the EDC from the corrected LMP. The Näegele's rule states—toget the EDC, add 7 days to the first day of LMP, and count back 3months. It has to be noted that after adding 7 days, the month canchange, and 3 months have to be counted back from that month. Whenmental calculation is done, it is easy to overlook such change in month.The Näegele's rule is very helpful when the pregnancy-wheel is nothandy.

Clinical bed-side evaluation—a shrewd clinician can always diagnose IUGRby abdominal examination of the patient, in case the history is completeand reliable. To avoid observer bias, a single blind study can be used,in which unmarked paper strips can be used to mark the fundal heightthat can later be measured over a marked calipers. Or, the paper measurestrip can also be used, one side unmarked for blinding. In obstetrics, aplacebo effect on the fetal subject or the mother is not an expectedclinical consequence.

Ultrasound Evaluation of Gestational Age

When dates are uncertain, and as ultrasound estimation of fetal age byweight is discrepant in IUGR, standard ultrasound measurements mayprovide additional information about the true gestational age of thefetus for correctly planning for early delivery true to the gestationalmaturity. Due to the brain sparing effect of IUGR, the ratio of the headand the abdominal circumference (HC/AC) is in the 90^(th) percentile in60% of cases of fetal IUGR. Trans Cerebellar diameter (TCD) may bevaluable (as the nomogram of Goldstein et al, 1987) in an IUGR pregnancydue to the ‘brain sparing’ effect despite growth restriction elsewhere,and it remains consistent through out, independent of fetal IUGR. Thegestational age (in weeks) corresponds with the TCD in millimeters until22 weeks, but the TCD accelerates after.

Ossification of distal femoral epiphysis occurs predictably around 32weeks, and the proximal tibial epiphysis ossifies around 35 weeks. Thesetwo ossification centers can be noted as prominent echoes distinct fromthe rest of the bone image. Presence of distal femoral epiphysis ofgreater than 3 mm along with the presence of any proximal tibialepiphysis can indicate a mature lung in almost all IUGR fetuses (Galan HL, 2003).

Advanced Diagnostic and Prognostic Parameters in the Clinical Managementof Fetal IUGR

Vascular Doppler Ultrasound evaluation—Doppler ‘Flow VelocimetryWaveforms’

(FVW)—the vascular Doppler study depends on the observations that: (1)the emitted ultrasound wave can be reflected, and the wave frequency canbe changed, when a moving object within the circulatory system like theRBC is encountered by the sound wave; (2) the degree of change in thereflected and returning sound signal can be used to calculate thevelocity/speed and the direction of the reflector (the RBC); (3) theover-all vascular doppler FVW form shows a clear systolic and also aclear diastolic component. All these principles are used to evaluate theresistance to blood flow in the uteroplacental circuit, and in turn thedegree of placental insufficiency in an IUGR pregnancy. The effects ofsuch placental resistance are also mirrored in the fetal vasculature,though manifest with different intensity in different vessels, alsoshowing a different chronology as can be expected, based on theanatomical site of the vessel depicting the changes.

Doppler monitoring of Uteroplacental circulation—As pregnancy advancesthe uteroplacental blood flow gradually increases, mainly due to spiralarterial remodeling. Very early on, due to trophoblastic invasion, theendothelium and the smooth muscle layers of the spiral vessels arereplaced, with loss of spiral artery vascular resistance. The lacunaefurther created in the syncytiotrophoblast by the cytotrophoblasticinvasion and their filling with blood from maternal spiral arteriesresult in dilated blood pools of maternal sinusoids that are responsiblefor the shunt effect of the placenta. In pregnancies complicated byIUGR, the trophoblastic invasion is limited to the decidual endometriumwith failure of the myometrial spiral arteries becoming low resistancevessels.

In normal pregnancy, the remodeling of spiral arteries dramaticallydecreases the peripheral resistance, an unique change that in turn canalso be reflected in the Doppler Flow Velocimetry Waveforms (FVW) of theuterine arteries. It can be meaningfully discerned and interpreted, ifthe pre-pregnancy wave pattern of uterine artery or any artery ingeneral is understood.

The normal non-pregnant (uterine) arterial pulse tracing: a normalarterial pulse tracing typically shows an upstroke followed by a downstroke. The UPSTROKE is abrupt without any secondary waves on it, andrepresents the initial part of ventricular systole. The DOWNSTROKE inthe middle has a sharp depression called as dicrotic notch or thepost-systolic notch, as this marks the early part of ventriculardiastole. The dicrotic notch is due to sharp fall of pressure in thearterial tree caused by the rolling back of aortic blood towards theleft ventricle at the beginning of ventricular diastole, when theventricular pressure sharply falls. The rest of the down stroke of thepulse tracing represents ventricular diastole when normally there is nofurther filling of the systemic circulation until the next systole, whenthere is an abrupt systolic upstroke again.

The typical uterine arterial tracing changes in pregnancy are mostly dueto the dilated placental sinusoidal shunt effect that continuously drawsin the blood with no rolling back towards the left ventricle in thispart of circulation, during the very early part of the ventriculardiastole. There is also some continued filling of the placentalsinusoidal spaces by the placental shunt-suction effect even through thelate diastole, as if there is ‘spiral artery stealing’ of blood from therest of the systemic circulation. These changes are shown in the uterineartery flow velocity wave forms (FVW) of a normal pregnancy, depictedas:

(1) loss of post-systolic notch (the dicrotic notch) in the middle ofthe down stroke of the tracing by about 26 weeks of gestation, and(2) continued end diastolic flow filling shown as lifting of the downslope of the last part of diastolic tracing far up from the base linethat continues until the next systolic upstroke.

However, these normal pregnancy changes are absent in the uterine arterywave forms of IUGR pregnancy that shows—persistence of post-systolic orearly diastolic notch, and little end diastolic filling, or absence ofincreased end diastolic flow velocity. The terminal diastolic wave staysvery near the base line due to little end diastolic filling.

The Following Indices of Doppler Flow Velocimetry Waveform (FVW) areUseful in Studying One or More of Local Circulatory Changes—

Systolic/Diastolic ratio (S/D ratio)—it is defined as the ratio of thepeak velocity of flow during systole and the peak velocity of flowduring diastole. Progressive increase in placental vascular resistancewith decrease in diastolic flow until the flow ceases, followed byreversal of the flow are ominous signs that need prompt furtherevaluation of the fetus. S/D ratio is the easiest to calculate, and isalso the most commonly used. In the Doppler velocity waveform, if Arepresents the peak systolic flow velocity, and B represents the peakdiastolic flow velocity, the systolic/diastolic flow ratio (S:D) is—

${S\text{:}\; D} = \frac{A}{B}$

The Pulsatility Index (PI) of the flow—can be formulated as:

${{Pulsatility}\mspace{14mu} {{Index}({PI})}} = \frac{A - B}{{Mean}\mspace{14mu} {velocity}}$

Uterine artery FVW analysis—it gained importance in screening forpreeclampsia and IUGR at 20-24 weeks gestation. End diastolic flowvelocities are not consistently present until after 15 weeks.

Doppler monitoring of Fetal circulation—From the fetal vessel DopplerFlow Velocimetry Waveform (FVW) it is possible to obtain the index ofresistance in fetal circulation, that in turn is the result ofresistance to circulation in the placental bed itself.

The Doppler Flow Velocimetry Waveforms are regularly used to assessresistance in fetal circulation, by monitoring more than one fetal bloodvessel. It is based on the fact that there are sequential and definitivechanges in doppler FVW resistance measurements in different vessels asthe fetal IUGR is deteriorating, and that they are predictably typicalin chronology.

1. Umbilical artery (UA)—60-70% of small placental arterial channelshave to be compromised before the UA flow becomes abnormal. The S/Dratio is considered as abnormal if it is >95^(th) percentile forgestational age, or if the diastolic flow is absent/reversed. Typically,the normal S/D ratio ranges as 1.5-2.5 in the third trimester. As theplacental vascular resistance increases, the S/D ratio also increases.With the umbilical artery zero diastolic flow velocity, the perinatalmortality is 10%, and when the umbilical arterial flow is reversed, theperinatal mortality is 33% (Cunningham et al). Patients witholigohydromnios, and normal umbilical artery Doppler S/D ratio are lesslikely to have poor perinatal outcome. PI>2 SD (standard deviations) isconsidered as abnormal.

The development of terminal villi and their capillaries (whosecontribution for the placental maternal-fetal exchange is significant)increases exponentially during 31-36 weeks of gestation, and it'sfailure could account for IUGR. It further contributes to the reducedumbilical artery end diastolic flow. Histometric support of thishypothesis is supported by observations of reduced terminal villivolumes as well as surface areas in IUGR pregnancies (Tesdale, 1984).Failure in the normal fall of maternal peripheral vascular resistance,usually by 16%, observed throughout normal pregnancy, can also beexpected in this context.

The umbilical artery was the first fetal vessel to be studied in thenormal and in the IUGR fetuses, and it was found out that the S/D ratiowas elevated above 95^(th) percentile in 85% cases of IUGR. Theumbilical artery changes can be interpreted as due to: (1) the increasedimpedance in the umbilical artery blood flow as a direct effect of theresistance in placental blood flow, and as the fetal effects of‘forcefulness of flow’(F), and ‘critical closing pressure’, the latterseen in small caliber vessels (‘law of Lawplace’) (see the discussion ina later section); (2) the changes in the viscosity of fetal blood, andsluggishness of the laminar flow, due to fetal polycythemia induced byfetal hypoxia; (3) the loss of the umbilical artery compliance, which inother words is the effect of critical closing pressure, as mentioned. Itis worthwhile noting that the umbilical artery has helically arrangedmuscles wherein 50% contraction causes complete occlusion, whereas 50%contraction of a simple circular muscle merely reduces it's lumencaliber (Von Heyek, 1935).

2. Middle cerebral artery (MCA)—it was adequately stressed earlier thatin the setting of uteroplacental insufficiency, the fetus adapts bydirecting more blood flow to vital organs like brain, heart and theadrenal glands by vascular auto-regulation. The fetal brain normally hasa high resistance flow pattern compared to other large vessels. However,the Doppler FVW form study of the IUGR fetus depicts in the middlecerebral arteries an increase in end-diastolic blood flow velocity thatin turn is reflected as low Doppler index of flow resistance. The MCAbeing positioned perpendicular to the mid-line of the brain, the Dopplerbeam can be easily positioned along the mid-point of the vessel, with aminimal angle.

Capponi and associates also showed that the MCA pulsatility index (PI)is decreased in IUGR, and it is the best predictor of fetal hypoxia.

The reduction in the fetal abdominal circumference (AC) precedes theDoppler abnormalities of both fetal umbilical artery and of the MCA. Thedecrease in the vascular resistance of MCA, and the increased vascularresistance of the umbilical artery, both were found to begin more than 3weeks earlier than the non-reassuring fetal heart rate recordings (Galanet al). The above fetal brain-sparing by cerebral auto-adaptation tohypoxia is a sign of appropriate fetal response, and loss or reversal ofsuch brain-sparing effect is considered as a late or ominous sign in adecompensating fetus, and a warning for urgent obstetric interference.With reversal of brain sparing auto-regulatory adaptation, fetalmortality approaches 50%. Loss of brain-sparing effect in the MCA can beconfirmed by checking Doppler FVWs elsewhere, especially on the venous(precordial) side, which waveforms will be found abnormal as well.

The ratio of MCA pulsality index (MCAPI) and the UA pulsality index(UAPI), that is, the ratio MCAPI:UAPI was found to be more valuable inrecent studies, by Shahinaj et al from Tirana, Albanie. It incorporatesdata that indicates not only placental state (in UA), but also theconsequent fetal response (in MCA), which is advantageous in predictingperinatal outcome.

As was noted earlier, in normal pregnancy the cerebral arteries showhigh resistance flow pattern at any time during gestation, withresistance higher than placental resistance, and a resulting MCAPI:UAPIratio of 1.08. The results of taking the above ratio into consideration(with ratio of 1.08 as normal, and <1.08 as abnormal) added positivelyto predicting the outcome.

The following are the reference abnormal values pertaining to thevascular Doppler velocimetry—

-   -   S/D ratio >2.6 or >95^(th) percentile in the umbilical artery        (UA)(abnormal)    -   Resistance Index (RI) >0.58, in the uterine artery (Ut. A)        circulation (abnormal)    -   Pulsality index (PI) >2 SD, in the umbilical artery (UA)        (abnormal).        -   >5^(th) percentile in the MCA (abnormal)    -   MCAPI:UAPI <1.08 is abnormal (Shahinaj et al)

The observations and deductions of the above researchers pertaining toMCAPI:UAPI needs further comment. It has to be noted that the fall ofMCA resistance indicates a compensated fetus. After documentation ofsuch observation, if fetal compensation fails, the MCA Doppler flowresistance will rise again, which is worse. Hence when interpreting theMCA Doppler FWV form with reference values as above, a longitudinalstudy with sequential changes in the values are meaningful (as theinterpretation can be discrete in reflecting the values true to thefetal state), rather than a random cross sectional value in isolationthat may not bear correlation to possibly deteriorating clinical events,unless UAPI also rises by that time, making the ratio <1.08.3.

Venous and cardiac flows—the Doppler velocimetry has been used to studythe venous circulation of the IUGR fetuses, like the circulation in theumbilical vein, the hepatic veins, the ductus venous, and the inferiorvena cava (IVC). Interesting correlation was found between the abnormalchanges in these vessels, and the fetal acid-base changes.

(a) Ductus venosus—A decrease in the velocity of a-wave is thecharacteristic abnormality in the ductus venosus. In the normal venousflow pattern, the a-wave form is characterized as below.

-   -   The ascent of a-wave—it represents the dynamic phase of atrial        systole, with rise of atrial pressure causing the regurgitation        of blood into the ductus venosus resulting a sharp positive        wave, then followed by a descent. The descent of a-wave—it        represents the subsequent fall in the atrial pressure during the        adynamic phase of atrial systole. Absent or reversed flow        velocity of a-wave indicates continued fetal deterioration.

Baschat and colleagues (2007) in their study involving 604 neonatesdelivered less than 33 weeks gestational age whose ultrasound abdominalcircumference (AC) was less than 5^(th) percentile, concluded thatchanges in the ductus venosus doppler velocitometry is primary inpredicting neonatal outcome. The changes were due to fetal myocardialdeterioration and acidemia. If the ductus venosus shows reversal ofblood flow at 26-28 weeks, it is a late sign, as the fetus has alreadysustained irreversible multi-organ damage. It implies that one may notwait for these changes to decide for delivery.

(b) Umbilical vein—normally the umbilical vein blood flow is monotonous,and the presence of pulsations or nicking corresponding with FHR issecondory to ventricular failure. It is a late sign of a decompensatingfetus. Changes caused by fetal breathing can mimic nicking or pulsationsof umbilical vein, and can be differentiated by looking for theircoincidence with fetal breathing motions. The rate of the umbilical veinpulsations seen in the umbilical vein Doppler waveform should berecorded when possible, when fetal breathing movements are of concern asin an unequivocal BPPS (biophysical profile scoring).

There are three identified umbilical venous patterns—(1) a monotonousumbilical vein flow pattern in a resting fetus (as normally thepositions of great veins are not retrogradely transmitted into distalveins, unless the great veins are enormously engorged); (2) anundulating umbilical vein flow pattern corresponding to fetalinspirations (transmitted from closely approximated liver and diaphragm)that are lower in frequency, and further confirmed by coincidence withfetal diaphragmatic movements; (3) the umbilical vein wave flow patterncorresponding in rate with that of the fetal heart rate itself asspecified above—the waves originate in the right atrium, and propagatein a retrograde manner into the venous tree, and in proper contextrepresent late stage of fetal heart failure, with associated fetalhypoxia and acidosis.

The Sequence (Chronology) of Fetal Monitoring for Predicting the FetalWell being/Time of Delivery in IUGR—

In monitoring an IUGR fetus, a study of Doppler changes cross-sectionalin time is important, but the chronology of the longitudinal changes(the serial changes in time) and it's reliable correlation with fetaldeterioration are even more important to assess the risk of prematurityvs. sudden fetal demise, and to deliver the severely distressed fetusesjust in time. In 2001 and 2002, three Doppler FVW studies clarified thata deteriorating fetus does show particular sequence of doppler changesprior to significantly abnormal non-stress test (NST), and an abnormalbiophysical profile (BPP) that would normally warrant immediatedelivery. The well biophysical profile (BPP) that would normally warrantimmediate delivery. The well differentiated chronology of Dopplerchanges is categorized as early and late changes as follows—

1. Early Doppler changes—

-   -   (a) Decreased abdominal circumference (AC)—in an asymmetrically        grown fetus.    -   (b) Umbilical artery        -   (1) increased PI (pulsatility index): manifests 3 weeks            before the abnormal FHR tracing.        -   (2) reduced end diastolic blood flow velocity.    -   (c) Middle cerebral artery (MCA)—(1) decreased PI (an indication        that ‘brain sparing’ is preserved): manifests 3 weeks before the        abnormal FHR tracing.        2. Late Doppler changes—    -   (a) Umbilical artery—Absent End Diastolic Flow Velocity (AEDV),        and following that the Reversed End Diastolic Flow Velocity        (REDV) are late signs that have showed effects upto 2 years of        postnatal life of an IUGR baby.    -   (b) MCAPI:UAPI (ratio)—recent studies proved the ratio reliable        and sensitive, but only the numbers of longitudinal follow up        rather than the cross sectional numbers in isolation can be        interpreted with discretion.    -   (c) Ductus Venosus Doppler changes—decrease in the a-wave        velocity.    -   (d) Umbilical vein Doppler abnormalities—show the presence of        pulsations or nicking in the umbilical vein FVW.        3. BPP (Biophysical Profile) abnormality.        4. NST (Non-stress test) abnormality.        5. FHR (fetal heart rate) tracing abnormality.        6. Oligohydromnios—since AF volume is the function of fetal        urine output and the renal perfusion, the presence of clinical        and U/S confirmed oligohydromnios should be of concern.

The Biophysical Profile (BPP)

The biophysical profile uses 5 components to be evaluated during astretch of 30 minutes duration. Each component is scored either as 0 oras 2, with a total best composite score as 10, and the worst as 0. Thescoring criteria are tabulated in table-6.

TABLE 6 The Biophysical Profile (BPP) Criterion score of 2 score of 0 1.Nonstress test (NST) reactive. non reactive. 2. Amniotic fluid atleastone 2 cm pocket no 2 × 2 cm (measured in two planes pocket.perpendicular to each other), that is, a 2 × 2 cm pocket. 3. Fetalbreathing ≧1 fetal breathing. abnormal or absent. 4. Fetal movements ≧3gross body or limb less than 3, movements during 30 minutes. or absent.5. Fetal tone ≧1 flexion or extension of abnormal the extremity, oropening or absent. and closing of hand.

The standard BPP score (BPPS) interpretation, and the normally pursuedaction plan—Score 8-10—normal; score 6—equivocal or suspicious, repeattest the next day; score 4—repeat test in 12 hours, and if score is ≦6,plan immediate obstetric interference.

Among the 12, 620 women tested weekly with BPP, Manning and co-workersreported the following statistical significance of the test: falsenegative rate-0.06%; false positive rate-40% with BPPS of 6, and 0% withBPPS of 0.

The fetal umbilical vein (containing oxygenated blood) blood pH showsthe following correlation with the BPP score (Manning et al): BPPS8-10-pH 7.37 (in the normal range); BPPS 6-pH 7.33; BPPS 4-pH 7.28; BPPS2-pH 7.2; BPPS 0-pH 7.08.

The Non-Stress Test (NST)

Basis for the test—if the fetus is neither acidotic nor hypoxic, thefetal heart rate accelerates with the fetal movement.

In association with or following fetal movements, the fetal heart rateshows transient heart rate accelerations, and there should be at least 2such transient fetal heart rate accelerations within 20 minute periodafter the test is started. Each heart rate acceleration should normallylast at least 15 seconds, with the peaking of the fetal heart rate by atleast 15 beats per minute above the base line. Conventionally, it isdone once a week, but doing twice a week reduced fetal demise bythreefold. It implies with certainty, but not always, that the fetuswill survive in-utero until the next test, that is until one week. Butin high risk pregnancy remote from term, the test can be repeated evendaily, or twice daily. However, the NST observations must be interpretedas per the gestational age, because fetuses less than 34 weeks do notalways respond by ‘accelerations of 15 beats lasting 15 seconds’criterion. It is prudent to allow 40 minute or longer wait period forfetal sleep cycle, to conclude as an insufficient fetal reactivity. Atime saving, and more reliable way of doing BPP/NST is the belowdescribed acoustic stimulation test (AST).

The acoustic stimulation test (AST)—some times the fetal sleep cyclescan be longer, and to eliminate the possibility of a false nonreactivetest, loud external sounds have to be used to startle and wake up thesleeping fetus. A commercially available acoustic stimulator can be usedto elicit acoustic stimulus on the maternal abdomen, repeated upto 3times, for upto 3 seconds (ACOG 2007). With the use of the AST, thestandard time duration mentioned in the above table can be observed forall the relevant tests, without a wait period of 40 minutes or more.

False negative tests are exceptionally low with NST. Large clinicaltrials inferred false negative results to be less than 0.7%. NST alsomore frequently identified a fetus in jeopardy than the Doppler FVWpattern had identified.

The Fetoplacental Pathogenesis as Depicted in the Doppler FVW Form andin BPP Score Abnormalities, and their Possible Remedial Measures—

Fetoplacental pathogenesis as depicted in Dopplerultrasound—Undoubtedly, the fetal vascular Doppler abnormalities hadoriginated from placental resistance, but there is also no doubt thatsubsequent fetal contribution significantly worsens the picture, makingit a vicious cycle. The vascular resistance that manifests in theumbilical artery has two components—placental and fetal. The placentalcomponent needs no further explanation. The fetal component is multifactorial, but the root cause is hypoglycemia with no energy reserve orlack of ATP for efficient contraction/tone anywhere in the fetalmusculature (poor tone, reflected in BPP) including the myocardium, thatresults in poor cardiac contractility, suboptimal stroke volume, and lowcardiac out-put. To start with, the systolic output needs to besufficient, so that there is enough reserve volume in the systemic treeduring diastole, after the blood runs off into the smaller vessels andveins.

The flow through a vessel is dependent on two factors—(1) the pressuredifference between the two ends of a blood vessel concerned, that is,the umbilical artery in this setting, and (2) the impedance to flow,that is, the vascular resistance within the vessel, expressed as:

$F = \frac{{P\; 1} - {P\; 2}}{R}$

wherein, F represents the rate or forcefulness of flow through a vessel,P₁ the pressure at the origin of the vessel, and P₂ the pressure at theother end of the vessel, and R, the impedance to flow. It has to benoted that it is the difference in the pressure between the two ends ofthe vessel, and not the absolute pressure within the vessel thatdetermines the rate or forcefulness of the flow (Guyton A C). Toexemplify the statement—if the blood pressure at both the ends of avessel is 60 mm/Hg, the flow ceases, though there is high absolutepressure of 60 mm/Hg within the vessel. If the blood pressure is 80mm/Hg proximally, and 60 mm/Hg distally, blood flow distally ispossible. It can be noted that an optimal pressure at the proximal aortacan be only achieved by effective stroke volume that lasts in thearterial tree through the cardiac diastole also (i.e. what has remainedafter the blood runs-off into the capillaries and the veins duringsystole). No doubt there is high pressure distally in the fetalumbilical artery due to placental resistance, but there is low pressureproximally at the fetal descending aorta level also, due to inefficientfetal cardiac contractility. This in turn can be due to many factorsthat can build up as a vicious cycle. ATP needed for effective cardiaccontraction can not be generated for various reasons like—(1) fetalhypoglycemia, (2) failure of pyruvic acid to enter or continue in citricacid cycle due to fetal vitamin/mineral deficiency, or else (3) fetalhypoxia. To compensate hypoxia, the fetus responds by tachycardia todraw more of oxygen from the placental bed. But tachycardia can onlyhappen at the expense of diastolic time (systolic time is constant whatever be the heart rate), drawn from each cardiac cycle, and in turn atthe expense of coronary filling, because coronaries fill only duringdiastole. That means, the fetal heart is working more, but any more thanoptimal average rate of 140 per minute can lead to coronary ischemia ina hypoxic fetus, and what seems as compensatory tachycardia does notserve the purpose of increased myocardial oxygenation, but willcertainly cause increase in long-term cardiac work load, leading firstto compensated cardiac failure, and later, decompensated failuremanifesting as bradycardia. As the great veins and the venous treecomprise high compliance and high capacitance vessels, the venous sideaccommodates many times more blood than the arterial side, during theprocess of compensated or decompensated cardiac failure that furtherreduces the blood getting into the heart. This in turn leads toprogressive diminishing of cardiac stroke volume during systole.Essentially, the fetus is in hypotensive state that is responsible forineffective maintenance of diastolic blood pressure that is shown asdecreased diastolic flow velocity of the doppler waveforms, or even asreversal of flow. Thus the fetal hypoglycemia and hypoxia withineffective cardiac contraction, and low P₁-P₂ can be directlyproportional to the diminished forcefulness of the flow, which is addedto the inversely proportional high peripheral resistance R, contributedby the placental resistance. Fetal polycythemia and the increased bloodviscosity also contribute to decreased flow velocity, and the high fetalsympathetic tone due to continued intrauterine stress can additionallycontribute to persistent fetal tachycardia. With fetal heart rate as 140per minute, each cardiac cycle lasts 0.428 seconds. If fetal HR goes upto 160 per minute, the cardiac cycle lasts only for 0.375 seconds. Thedecreased time of 0.053 seconds which is 12.38% decrease of the normallyallowed time for each cardiac cycle (with the optimal 140 beats perminute) is happening by consistent cut off from the ‘diastolic coronaryfilling time’. That is, for the fetus, it is 2 hours and 58 minutes perday loss in the coronary filling time. It is imposed on the top of thelong-term strain of increased cardiac work load of 20 extra beats perminute. Restoration of fetal heart rate to optimal number early on canprevent fetal myocardial work load.

It is worthy of note that the umbilical arteries being the branches offetal internal iliac arteries, are not high caliber vessels to startwith, and in turn they are subjected to the physical laws of ‘criticalclosing pressure’ seen in small caliber vessels, as is dictated by thelaw of Laplace. Though each umbilical artery receives 20.5% of the fetaltotal cardiac out-put (Rudolph and Heyman, 1968), the absolute flowthrough these vessels is very less, that is only 100 ml per minute/kg at22 weeks, and 300 ml per minute/kg at 37-38 weeks (Gill and co-workers,1981). The above are even lower volumes, if calculated per fetal cardiaccycle, flowing into the placental circuit. One may consider that theyare proportional to the fetal size, but the dynamics and the physicallaws of blood flow are neither different nor forgiving, because they aredirected to the fetal vessels. In an adult, at 20 mm/Hg blood pressure,blood flow in the smaller vessels entirely ceases, that being the‘critical closing pressure’ (Guyton A C). The vasomotor tone of thesmaller arteries is always attempting to constrict these vessels tosmaller diameters, whereas the blood pressure inside is attempting todilate them. When the pressure in a vessel falls, also decreasing thevascular diameter, the muscular forces tending to keep the vessel wallstretched, decrease extremely rapidly (Guyton A C).

The law of Laplace states—the circumferential force (F) tending tostretch the muscle fibers of a vessel wall is proportional to thediameter (D) of the vessel times the pressure (P) with in the vessel. Itcan be shown as: F∝D×P.

The law explains that more the blood pressure falls decreasing theeffective diameter of a vessel, further more the vessel wall will close,which also is a vicious cycle. To make the situation worse, theumbilical artery has helically arranged muscles wherein 50% contractioncauses complete occlusion, whereas 50% contraction of a simple circularmuscle merely reduces it's lumen caliber (Van Heyek, 1935). Hence, it isimperative that adequate fetal cardiac contractility, optimal strokevolume, and normal range diastolic blood pressure are maintained infetal arterial tree, and in turn in the small caliber umbilicalarteries.

BPP—Impaired energy reserve/ATP is responsible for lowered over-allfetal movements, and the lowered muscle tone (just as the lowered fetalcardiac muscle contractility described above) that are reflected in thelowered score of BPP. Essentially, the low BPPS represents a fetus oflow energy, i.e overall fetal apathy.

The Possible Corrective Measures—

Maternal rest in left lateral Trendelenburg's position—It may be notedthat in a cephalic presentation with the placenta located in the upperuterine segment, when the mother is in standing or sitting posture, theblood in the aorta and the hypogastric vessels (that form umbilicalarteries) of the fetus have their blood flow towards placenta, flowingagainst gravity. Gravity may also make the loops of umbilical cord tosettle in the lower uterine segment (unless interrupted by fetal bodyparts) from where the blood has to flow upwards towards the placenta,also against gravity. Hence this writing advocates maternal bed rest inleft lateral Trendelenburg's position (head end inclined lower than thefoot end, best achieved by raising the foot end of the bed by solidblocks) that can have impact in overcoming the forces of gravity, andthe placental resistance. Though the fetal position is unstable earlierin pregnancy, yet in this position the placenta and the umbilical cordwill be still situated at a lower level than the fetal heart. Theuterine artery course that becomes descending instead of ascending cancompensate maternal abdominal aortic flow that becomes ascending. Thismaternal positioning also takes into consideration of the facts that thematernal cardiac function is appropriately hyperdynamic to pumpefficiently into the ascending thoraco-abdominal aortic column, and theuterine circulation that is locally sub-optimal for whatever pathologyis deservingly benefited by the descending column of blood within theuterine artery. With the loops of the umbilical cord also displacednearer to the placental plane of the upper uterine segment, the bloodflow is not against gravity which can improve the flow impedance in theumbilical artery. While the foot end of the bed is raised by blocks, themother should have one or two pillows under her head and neck, to avoidpressure effects in the head in due course, like facial puffiness, nasalcongestion etc, symptoms that manifest even during normal pregnancy.Trendelenburg's position though theoretically appealing, can beimpractical. Hence, at least bed rest in general can have tremendousbenefit, if advocated with correction of other major deficits.

It is also helpful to inquire if the mother has gastroesophageal reflexdisease (GERD) to be treated with medications for GERD, and to beadvised to sleep as advocated above.

The term lower uterine segment though generally used in obstetricsduring labor, in this writing, it is used throughout to denote the loweranatomical part of the uterus, and must be so understood.

Correction of unobvious maternal factors, though considered asinsignificant, they can still help, in case they are few of the manyculprits operating in unison. It is the tight fitting maternal clothing,especially the pre-pregnant bra that she had long ago outgrown duringpregnancy. Full chest expansion, especially to allow for the neededpregnancy adaptation of respiration, is very important, and the frontwire-rimmed bras have to be especially discouraged, as they restrict thefull expansion of the anterior hemithorax with decremented tidal volume,defeating the fine tuning of the nature's concert of pregnancyorchestration. The progesterone-driven pregnancy hyperventilation has apurpose. The pregnancy minute volume increases by 40% almost entirely byincrease in tidal volume rather than respiratory rate, that causesdecrease in expiratory reserve volume, with alveolar ventilationincreasing by 65%, and PCO₂ decreasing significantly for the neededgradient at the placental level (Hytten F. E). Low oxygen concentrationin any area of the lung due to hypoventilation causes pulmonaryvasoconstriction in that area, an adaptation to direct the blood flow tobetter aerated lung fields, a feature unique to pulmonary circulation.If the hypoventilation (with reduced PO₂ of alveolar air) is generalizeddue to mechanically restricted chest expansion, generalized pulmonaryvasoconstriction can ensue, with resultant lowered PO₂ of maternalarterial blood, that will be added to the higher value of PCO₂, bothvalues not adapted to pregnancy range. If there is shortness of breathdue to ill-fitting clothing, the mother may attribute it as the naturalconsequence of pregnancy itself.

The mother should be further advised to wear increasing sizes of bras asthe pregnancy advances. The best way to demonstrate that she is wearinga tight fitting bra is to let the nurse unhook the bra, and observe howmuch apart the bra ends will recede from each other during fullinspiration, and to let the mother be surprised to feel that gap withher hand, and know the measure of chest circumference she is notallowing to expand. The nurse should be trained to observe/document theconcerned observations. The chest expansion/measurement can be morewhile sitting than standing. The best option of the mother is to try thebra size while sitting, and buy one size larger.

Tight fitting jeans (or outgrown dress pants, or tight dress skirts)should also be curtailed, as they can press the gravid uterus againstthe great vessels. Such tight garments can have an effect worse thansupine hypotensive syndrome, as the pressure on the uterus can be allthrough the wakeful hours. The patient may be considering to replace herregular garments only when it becomes impossible to wear, withoutknowing the adverse effects on her pregnancy, and with compensatedasthma, COPD, heart diseases, smoking etc. the effect on pregnancy canbe significant. In fact, these subtle factors can be operating in IUGRwith no known etiology.

The D-Glucose Supplements and the IUGR Diet Directly or IndirectlyAccomplish the Following Beneficial Effects, as Reflected Through theDoppler Velocimetry—

(1) By maternal hypertonic D-glucose supplements, an adequate supply ofD-glucose to both the fetus and the placenta is ensured. It is to benoted that placenta consumes 50-60% of glucose getting into theplacental interface, and 80% of it is converted into lactate that issupplied to the fetus during times of need. Fetal heart (and also thefetal brain and skeletal muscle) efficiently metabolizes lactate just asit metabolizes glucose (see also the section ‘The improvement of fetallactic acidosis/pyruvic acidosis). Maternal IV glucose supplementsduring midnight, or IUGR-diet snacks in between meals can be valuable inthis regard to ensure almost continuous fetal D-glucose supply, or elseto improve placental lactate reserves, stored with no O₂ expended by theplacenta.(2) Cessation of fatty acid oxidation saves 33% of oxygen, improvingmyocardial oxygenation, fetal tachycardia, coronary filling, and fetalcardiac function needed for optimal stroke volume.(3) With glucose availability, fetal body protein break down for direenergy needs is curtailed, the amino acid source of energy being worsethan the lipid source in it's ATP/O₂ expenditure.(4) Fetal energy for swallowing of the AF improves.(5) Placental active transport of many elements, mostly of minerals andvitamins that the placenta concentrates, is dependent on placentalavailability of glucose to generate ATP continuously, needed for suchactive transport. Iron, calcium, magnesium, and B-complex factors areall vital and scant in the maternal compartment and the active transportis the only means of their fetal acquisition. Though the compensatorypolycythemia in IUGR is mainly a reflex fetal response to hypoxia, it isessential that the fetal RBC has the needed optimal MCHC with theimproved iron moiety of hemoglobin also contributing for the relief offetal polycythemia that in turn relieves the sluggish laminar flow inall vessels. The implemented oxygen therapy in the treatment protocolwill further benefit persistent fetal hypoxia, and it's accompanyingadverse fetal effects.(6) The IUGR diet with rich supply of essential amino acids of whicharginine is a part, will contribute to the compensatory synthesis ofnitric oxide (the body's integral element needed for vasodilationthroughout) in the terminal villus vasculature as well as in theumbilical vessels improving the umbilical artery compliance, enddiastolic flow velocity/volume, and hypoxia.

The hyprtonic D-glucose and IUGR diet exert their invaluable effect,first of all by breaking the vicious cycle of established adverse pathways, after which the fetal milieu can be better amenable to anypositive physiochemical benefits of such therapeutic maneuvers. Hencetheir therapeutic trial is warranted (especially when a fetus is notviable for delivery) either the fetus is in compensated, ordecompensated (cardiac) failure, and what ever be the nature of DopplerFVW form at the outset. Doing something is better than doing nothing, atleast for one reason to start with—for the relief of distress both tothe mother and to her clinician that is invariable in inaction, whereasat a later date, the unrelievable fetal distress may be found to besurprisingly relieved.

The Clinical Aspects of Hypertonic Glucose Supplements to the Mother

The novel invention sets forth desirable attributes for successfultreatment of a so far truly evasive disease entity in the specified artof obstetrics, encompassing a treatment that is: safe, simple, minimallyinvasive, risk free in terms of fetomaternal mortality/morbidity,non-anxiety provoking, and most important of all, one that was provedsuccessful, as evidenced by a successful case study of severe fetalIUGR, treated by the author inventor. Being simple, it's method iseasily reproducible over desirable long term with similar anticipationof success. Most importantly, the treatment is based on sound andinfallible scientific model conforming to the needed ‘as a wholeinquiry’ approached and clarified with biochemical/physiologicalrationale befitting every new encounter, as seen in the precedingsections.

In alleviating the placental insufficiency of fetal IUGR, an accelerated‘Facilitate diffusion’ of glucose can be achieved in the afflictedplacenta, by creating transient hyperglycemia in the mother byhypertonic glucose 25-50%, up to 50-100 cc twice or thrice a day, givenas a bolus intravenous injection over a period of 3-5 minutes, suchtreatment initiated as soon as it is confirmed that the fetal IUGR is ofvascular in origin. When the therapeutic trials of maternal IVtreatments are exhausted without substantial benefit, as later discussedin detail, transamniotic isotonic D-glucose supplements are initiated,the amniotic cavity accessed through a subcutaneously implantedpregnancy-port (SIPP) catheter via an extraperitoneal suprapubicapproach, with novel structural and operational modalities that are easyto implement.

Apart from the classic preeclampsia/eclampsia, the varied pathologicalstates subject to fetal growth restriction of vascular origin, and canbe similarly benefited are: chromosomal anomalies found to be associatedwith reduced number of small muscular arteries in the tertiary stemvilli, chronic placental separation, extensive localized placentalinfarction, circumvallate placenta, velamentous insertion of the cord,one or both the twins affected due to reduced trophoblastic areaavailable to each, to mention a few (this list is not construed to beexhaustive). They are unseemingly though clinically responsible for thediminutive placental exchange, and for the fetal IUGR. Clinicaldiagnosis of a vascular pathology is not feasible in all circumstances,and hence as a diagnosis of exclusion, any suspected fetal IUGR can beoffered a therapeutic trial.

Accounting legal implications—The treatment of fetal IUGR with maternalhypertonic glucose supplements is not without legal implications, if notdone discretely. This is due to the unavoidable interference with thematernal carbohydrate metabolism. The natural course of diabetes in apatient ultimately destined for it, during pregnancy or after, becomesimperceptible from what is benignly interfered with pertaining tocarbohydrate metabolism, through the treatment itself (refer 1(b) of thesection ‘The author's theory to account for the manifest maternalhyperinsulinemia during normal pregnancy’ to understand the naturalhistory of gestational diabetes). For that reason, adequate patienteducation and a strong therapeutic alliance with the patient areparamount. This needs the patient's equal participation in all decisionsfor her treatment. A strong basic knowledge is important to clarifypatient's questions/concerns, and for confident clinical management alsorequired in invoking patient's confidence, as for either, there is noshort cut.

Careful history taking with regard to family history of diabetes, andfor clues of previous gestational diabetes is important. IUGR in adiabetic pregnancy is rare, but possible, when hyperglycemia ismarginal, and such rare encounters that can put the obstetrician in adilemma, need in depth discussion. Whereas the hyperglycemia can be justfew numbers above cut off values, the induced hyperglycemia is morepronounced by it's higher blood sugar range, and hence significant inovercoming the placental impedance. In this situation, making decisionabout maternal versus fetal well-being can be daunting, and needssignificant understanding on the patient's part. It has to be honestlyinformed to the patient that postponing the treatment of her diabetes byfew months will not significantly affect the natural course of thedisease, as the disease consequences slowly evolve over very long term,and after delivery, every stringent measure followed through years willequally contribute to the best ultimate outcome. This is also assured bythe specialist (who should be called throughout, as ‘diabetesspecialist’ instead of an endocrinologist) for the needed patient trust,apart from relieving her anxiety and possible indecision. Carefulmonitoring to prevent adverse events of diabetes is necessary, andinformation pertaining must be given to the patient as writteninstructions, apart from her signed alliance to cooperate with/followneeded frequent monitoring. Above all, decision for treatment should beentirely made by the patient, along with her signing a therapeuticalliance for no physician responsibility for what ever be the course ofdiabetes (if worsened soon after pregnancy, or years later), or theoutcome of the baby. Indeed, the course can be unpredictable for numberof reasons, and one can be the patient's non-compliance itself later on,in the treatment of her mild diabetes. The patent's chart should bepreserved even after the obstetric relationship is over, as any patient,if needed to be treated with insulin for uncontrolled diabetes later onin life can be aggrieved for such need and out-come, and can pursuelegal course, forgetting all ‘therapeutic-agreements’ she made yearsago. Demonstration of fetal growth soon after treatment will be agratifying incentive both to the patient and to her obstetrician tofollow the same, until the fetal viability is assured for an earliestpossible delivery. These patients should be watched for hyperosmolarsyndrome, ketoacidosis etc. just like any other diabetic patient, andtreated similarly. Hyperglycemia is targeted only to the extent that thedesired fetal growth is achieved, and no more. Fetal anomalies due touncontrolled diabetes are as a result of uncontrolled ketonemia in thefirst trimester, and such danger is never a clinical consequence duringthe second trimester and later, when the patient is being treated.

A sincerely vigilant attitude, both clinically and personally towardsthe patient from early on is important to gain her trust, which alsoenables the patient to ungrudgingly and understandingly accept anyadverse outcome, and realize that her physician had done the best thatcan be possibly done, in her situation. A written summary of: thenatural course of diabetes, the unique effect pregnancy itself has onblood sugar control, the contemplated modality of treatment, and theimperceptibility of the effects of treatment from the natural course ofdiabetes for those destined for it—should be given as a hand-out to all,on the first encounter. The obstetrician should take time to answer allthe patient's concerns and questions, and then proceed with clinicaldecision making carefully but swiftly, as there is no time to waste, aseach day passed has it's toll on the fetus, and the ultimate pregnancyoutcome, a matter that needs to be conveyed to the patient also.

Maternal Diabetes Screening—

In the majority, as the onset of fetal IUGR falls around the time thatthe mother is screened for diabetes at 28 weeks, the obstetrician isalready aware of the patient's glucose tolerance, and if not, it can beimmediately ascertained. The screening is done with 50 g oral glucose,without regard to prandial state, or time of the day. To test, a singlevenous sample is drawn at 1 hour.

The normal blood glucose level cut-off at—130 mg/dL—has 90% sensitivity,and

-   -   at—140 mg/dL—has 80% sensitivity (Metzger B E et al).

The American Diabetic Association (ADA) and the ACOG agree with eitherof the threshold values. For all positive tests, WHO and ADA recommend a3 hour OGTT (oral glucose tolerance test) with 75 g of glucose and thediagnosis of diabetes mellitus is made when two or more venous plasmaglucose values are at or above the following standardized values,approved by the ADA—

-   -   Fasting—95 mg/dL; 1 hour—180 mg/dL; 2 hours—155 mg/dL; 3        hours—140 mg/dL.    -   In a patient whose screening was normal, but is diagnosed with        persistent impaired glucose tolerance post-partum—it is        difficult to ascertain whether it was due to diabetes that the        patient was destined to develop during pregnancy, or it was due        to pancreatic beta cell stress induced by the treatment.        Whatever be the cause, healthy patient with sufficient        pancreatic reserve/no inherent predisposition should not develop        overt diabetes before or after delivery. It is only a        susceptible patient whose reserves are exhausted by therapeutic        challenge, will be developing diabetes, but earlier. Such        possibility also should be explained to the patient before        treatment, not overlooking to clarify that the unmasking of the        disease happened only earlier, but would be otherwise inevitable        a short time later. It is the risk the mother should decide to        accept for the sake of delivering a viable and reasonably        healthy infant. A mother with previous adverse pregnancy        outcomes would not mind it at all, especially after delivering        her well grown child. The postpartum diabetes management in        these patients is no different, and an endocrinology consult and        also a dietary consult can be better done as a group        consultation in this unique clinical situation, involving the        obstetrician also initially, so that he or she is aware of the        input and the counseling given to the patient. Similar group        consultation is better for pre-natal patients also, at least        once, and the obstetrician in turn should clarify to the        specialists what is being expected, and if satisfied, it is        time-saving to involve same specialists for all patients.

Important Patient Parameters to Account for Before/During Therapy—

1. Thiamine—all patients should be given 100 mg of IV/IM thiamine (B₁vitamin) before IV hypertonic D-glucose treatment. This is done evenwith prior oral supplements in a compliant patient. The obstetricianshould document such therapy in terms of point in time, that is, priorto IV glucose treatment. It is for the reason that after glucose load,thiamine deficiency can precipitate pyruvic acidosis/lactic acidosis ina previously malnourished patient. Malnutrition is not uncommon in thissubset of population due to alcoholism, hyperemesis, and pregnancy picain the socioeconomically well-to-do cultures, but under-nutrition can bea contributing factor in the developing countries.2. Multivitamins/minerals—all patients should have IVmultivitamins/minerals supplements that includes generous amounts ofphosphorous (assuming patient's renal function is optimal).3. Magnesium—magnesium supplements is considered separately due to it'sspecific deficit in malnourished patients, and due to the vital role ofmagnesium in all biologic functions where ATP is involved, which isubiquitous, as it is Mg-ATP that actually participates in suchreactions.4. Potassium levels are needed to be monitored initially during IVhypertonic glucose treatment to note occasional undue fluctuations.

IV hypertonic D-glucose treatment, and the blood glucose parameters—Theamount of IV hypertonic 25-50% glucose supplements given to the patient(mother) as 50-100 cc bolus twice or thrice daily should beindividualized. As evidenced by the treatment done by the author, suchmaternal therapy is deemed very safe, and well tolerated in individualswith no inherent predisposition to impaired glucose tolerance. However,it is a good idea to start with smaller dose such as 50 cc of 25%glucose, and to progressively but swiftly increase to 100 cc of 50%glucose. Such progressive therapeutic augmentation is done in thehospital, as the devised protocol, with also monitoring of blood glucosevalues, and of the potassium response initially.

With 25 G of glucose (equal to 25% glucose as 100 cc, or 50% glucose as50 cc of therapeutic hypertonic glucose supplements), injected as IVbolus over a 3-5 minute period, the following blood glucose levels canbe expected—a peak of 175 mg % at 15 minutes, 125 mg % at 30 minutes,and back to normal non-pregnant level of 75 mg % at 1 hour, and furtherdeclining to slightly lower levels of 70 mg % during the second hour.These levels were the average results of 120 pregnant women testedduring pregnancy by Spellacy W N et al in 1964-65.

The above numbers also demonstrate that in a healthy pregnancy (withrespect to glucose metabolism, and not IUGR) the normal glucose levelsare attained in the maternal circulation within one hour. In the sametoken, advocating the therapy in between meals and at mid-night, andadditional frequent intake of IUGR-diet snacks will create more of suchhyperglycemic peaks in the mother, without inducing adverse effects onthe carbohydrate metabolism. In fact, the IV hypertonic glucosesupplements mimic post-prandial glucose peak, and can be compared to asituation where a mother has a tremendous appetite and is eating threemeals and also equal sized snacks in between. That type of food intakeis not uncommon during pregnancy, and the body's response to short-termglucose fluctuations spanning limited duration such as during the laterfew months of pregnancy is very forgiving, though it may not be the casewith the patient's predisposition to diabetes. Mid-night infusionsimpose inconvenience to the mother, but they truly aim in preventingearly morning hypoglycemic phase that can be otherwise prevalent even inhealthy pregnant women. During such short but many of hyperglycemicpeaks in a day the placenta can transmit D-glucose in an exceeding‘speed mode’ of Vmax (refer the Michaelis-Menten model discussed in theforegoing section) when the surplus of the hexose sugar is stored bothas fetal liver glycogen and the placental lactate that are utilized asthe circulating glucose levels tend to fall.

Management of IUGR Pregnancy Around the Time of Hospitalization

The management of an IUGR pregnancy clinches on the correct diagnosis ofit's existence. A correct diagnosis is made by any one or all of thefollowing—1. confirming the current gestational age as per the firsttrimester ultrasound, and the previously correlated uterine size, 2. thegestational age as per the CLMP which was earlier discussed, 3. anyreliable previously discussed U/S indicators of true fetal gestationalage.

When fetal IUGR is confirmed, the patient shall be hospitalized withdecreased physical activity and bed rest, as the fetal surveillance isstarted. This includes fetal movement charts, clinical andultra-sonogram assessment of fetal growth, amniotic fluid (AF) volume,non-stress test (NST), biophysical profile (BPP), fetal heart rate (FHR)monitoring, Doppler velocimetry, AF lactate/lactic acid (AF-LA) levels,and also clinical evaluation of the mother. Full profile of thisexhaustive list of tests (see table-7) can be tailored to thephysician's discretion, as clinically warranted.

In most cases of IUGR, as pregnancy can be quite remote from term, andfetal viability improbable (with prematurity added to growthrestriction), irrespective of the base-line lab values i.e.unsatisfactory doppler velocimetry, or non-reassuring FHR/BPP,hypertonic glucose treatments are advised. As discussed, it'smultifaceted effects upon IUGR pregnancy is unparalleled. The aim is toreverse pathology of whatever severity, at any stage of pregnancy. Thepatient needs to be disclosed that pregnancy outcome is veryunsatisfactory without it, though however, as with any treatment, 100%response and assured positive pregnancy outcome may not be guaranteed,because the inclusion group is of varied pathology, some inherentlyunresponsive. The patient may also be informed that statistical data ofthe treatment is not available at the time, but it can be verypromising. Clarify that there is a possibility of fetal demise with orwithout treatment, and hence treatment is strongly advised, as at leastthere will be satisfaction of trying what is feasible, and that thetreatment will be continued only until fetal viability, for electivedelivery.

Base line diagnostics—all baseline diagnostics are documented in thecomprehensive 7 day ‘The fetal monitoring/treatment intervention table(table-7), devised for the regular outpatient or for in-hospitalcharting, for any needed diagnostics and for the indicated plans ofintervention.

Starting the patient on IUGR diet—Special emphasis should be made thatalong with the diet that usually contains complex carbohydrates, intakeof rapidly absorbable simple hexose sugar as 25 grams of glucose powderin water before each meal and each snack—should be a mandate of thedietary protocol. The diet also includes at least 1 egg with each mealand breakfast, for ensured essential amino acid intake (the egg being a‘reference protein’ in terms of it's essential amino acid content, andbeing acceptable even for a habitual vegetarian) to ensure one of thebenefits among many—the arginine supply needed for feto-placental nitricacid synthesis, for relieving placental and umbilical vascularimpedance. Arginine is also an insulin-secretagogue, whose action can bepreserved even when glucose stimulated insulin secretion is impaired(Powers A C). This works in favor of improving maternal glucosetolerance in those with a predisposition for gestational diabetes.

the Protocol of Maternal IV Hypertonic D-Glucose Therapy Preparations ofD-Glucose—

The hypertonic D-glucose is supplied by the manufacturers in a prefilleddisposable syringe with optional stick-guard safety needle (MIN-I-JET)in the standard strengths of 25% (2.5 g in 10 ml) and 50% (25 g in 50ml) solutions, as below—

-   -   25 g of 25% strength (denoted in this treatment protocol as        DG₂₅)—supplied as 10 vials of 10 ml, each 10 ml vial containing        2.5 g of glucose (a total of 25 g of D-glucose in a total of 100        ml).    -   25 g of 50% strength (denoted in this treatment protocol as        DG₅₀)—supplied as 1 vial of 50 ml (a total of 25 g of D-glucose        in 50 ml).

The Patient's Food, and the D-Glucose IV Supplement Timings—

-   -   Breakfast-lunch-dinner times are at: 7 am-1 pm-7 pm,    -   DG₂₅₋₅₀ supplements are at: 10 am-4 pm-1 am (initially twice,        and thrice dosings latter).    -   Snacks—when ever the patient is hungry, but preferred at 4 pm        (for those with twice dosing only), 10 pm and 4 am (for both        twice and thrice dosings). The above food schedule is consistent        with hospital routine of patients' meal supply, with the        D-glucose supplements given midway between each meal, so that        too many maternal fasting hours are not allowed at any time.

The amniotic fluid lactic acid/lactate (AF-LA) level, or lacticacid/creatinine ratio (L/C ratio) as therapeutic aid in clinicaldecision making—AF-lactic acid levels or L/C ratio can be a tool ofdecision making, and can be specifically directed to finding the lacticacid level before and after D-glucose therapy, for adjusting the dose ofthe supplements, if there are also accompanying changes in BPP scores.With the therapeutic benefits of D-glucose on fetoplacental ATPgeneration/arginine transport, NO synthesis, and vasculogenesis leadingto fall in placental impedance, the patients if started on O₂ therapydue to elevated lactic acid levels, can be swiftly or gradually weanedoff from either the intermittent oxygen therapy (IOT), or continuousoxygen therapy (COT) while D-glucose treatments are continued, as theaim is to send the patient(s) home, stabilized on an optimal buttolerable dose of DG₂₅₋₅₀, without home oxygen therapy the latter beingnot feasible in all cases. With elevated AF lactate levels (>10.1mmol/L, Pardi et al, 1987) only COT is started initially, with IVglucose therapy supplemented after the lactate level normalizes.

Any patient if resistant to IV DG₂₅ treatment even with continuousoxygen therapy (COT), it clearly indicates significant fetalhypoglycemia due to placental insufficiency that needs to be interferedwith intraamniotic isotonic D-glucose treatments. Normal or below normalAF lactic acid level clinches that the problem is hypoglycemia, with orwithout hypoxia.

The Maternal IV DG₂₅₋₅₀ Treatment

With normal/normalized AF lactate levels, the patients are divided intofollowing groups based on the gestational ages and the baseline BPPscores.

-   -   26-31 weeks gestation—with BPP score≧8 (26-31, Group A),        -   with BPP score ≦6 (26-31, Group B).    -   32 and (+) weeks gestation—with BPP score≧8 (32, Group A),        -   with BPP score≦6 (32, Group B).            Maternal IV Hypertonic D-Glucose Treatment Protocol for the            Gestational Ages of 26-31 Weeks, and with the Baseline BPP            Score ≧8 (26-31, Group A)—

With normal BPP score accompanied by IUGR, it can be considered that thefetal growth restriction is mild to moderate. This fetus is obviouslynot acidotic, as there is a direct correlation between the BPP score andfetal acidemia. It can also be reasonably expected that the fetustolerates hypertonic glucose treatments in moderate doses withoutrequiring oxygen therapy in the manner it may be otherwise required withvery low BPP scores accompanied by severe hypoxia. The following is themost feasible therapeutic interventional protocol for this group ofmothers—

DAY-1: Start DG₂₅ as 50 ml (12.5 g of D-glucose) thrice daily (10 am, 4pm, and 1 am).DAY-2: 8-9 am—check BPP. If score remains as baseline, continue sametreatment on day-2.DAY-3: increase the dose to DG₅₀ as 50 ml (25 g of D-glucose) thricedaily.DAY-4: 8-9 am—check BPP. If score remains same, continue the treatmenton day-4.DAY-5: if the patient is stable with no FHR changes (as describedbelow), and with BPP score of ≧8, the patient is discharged home withthe last maximal dose tolerated, to be further increased to DG₅₀ as 75ml thrice daily, and later DG₅₀ as 100 ml thrice daily, as pregnancyadvances.

Intermittent FHR (fetal heart rate) monitoring—it is done for four hoursstarting ½-1 hour before the therapy initially, and later, whenever thedose increments are made. For any adverse FHR changes, IOT (theintermittent oxygen therapy) is started with 6 L O₂ by nasal cannula tobe continued for 2 hours and then to be tapered every ½ hour as 6 L-5L-4 L-2 L-stop. Weaning from IOT, or advancing to Continuous OxygenTherapy (COT) with slow increments of DG₂₅₋₅₀ in the latter situation,is in a manner similar to that shown in the algorithmic flow sheet forGROUP-B, in the subsequent section.

The rationale of BPP monitoring as a proxy for AF-LA/pH levels—Thoughthe initial decision making was based on the AF-LA level, the subsequentfollow up is not feasible to be solely based on AF-LA levels. Anydeficit, either fetal hypoglycemia or hypoxia, by failing to generateATP is reflected in the fall of BPP score, due to fetal hypotonia.Oxygen therapy can be added at this point to the ongoing D-glucosetherapy. The physician can check AF lactic acid levels, thoughinfrequently, when the BPP score shows no improvement with sufficientlytitrated oxygen therapy.

In cases with both the FHR change, and fall of BPPS by 2 or more, at anytime during treatments of DAY 1-5, as above: the FHR changes are treatedwith intermittent O₂ therapy (IOT), as above. The thrice daily D-glucosedose can also be changed to twice daily, to be administered at 1 am and10 am, and the response observed with further monitoring. This patientmay be increased to higher dose very gradually. Other needed testing canbe also incorporated, if felt appropriate. The subsequent plan issimilar to the plan outlined in the algorithm flow sheet below, forGROUP-B.

Days 1, 2, 3 (or more) (for example) can be more days in the real timepatient care, with unforeseen delays of response. This seeming time-lineis indeed a therapeutic mode line. Numbers for the days were introducedbecause they are better tools of chronology, and of mutual communicationin unambiguous terms. The time-line only indicates suggested minimaltime, and similar plan can be continued with more time allowed forspecified increments.

At the end of 1-2 weeks of hospitalization, or as needed—the fetal sizeis checked by ultrasound, as there will be discernable increment infetal growth parameters by 2 weeks at times the catch-up growth morethan normally expected. Such observation of response is the bestprognosticative indicator compared to any other standard monitoringmodalities, to continue the maternal hypertonic IV glucose treatment.

Maternal IV Hypertonic D-Glucose Treatment Protocol Algorithm for theGestational Ages of 26-31 Weeks, and with the Baseline BPP Score ≦6(26-31 GROUP-B)—Algorithm Flow Sheet for Group-B, 26-31 Weeks (BPP Score ≦6): ForD-Glucose 25% (DG₂₅) Maternal Intravenous (IV) Therapy, Starting TwiceDaily (1 am & 10 am), with Progressive Increments

IOT—as a routine, intermittent O₂ therapy as 6 L/minute by nasal cannulais done soon after a noted fallen BPP score (to be tapered as described,after 2 hours), and again during each DG₂₅₋₅₀ therapy, to be taperedalso after 2 hours.

Intermittent FHR monitoring—in addition to BPP, intermittent FHRmonitoring can be started ½-1 hour before the treatment in a similarmanner as specified for the preceding group. For any adverse FHRchanges, IOT as 6 L O₂ is started as above.

COT/IOT weaning by Every Day Challenge (EVDC) of CAT-3—In the aboveprotocol algorithm, for CAT-3 while trying to change COT to IOT, whenevery day weaning attempts (EVDC) are commenced, patient's COT istapered starting at 6 am, with ½ hour decrements as 6 L-5 L-4 L-2L-stop. FHR tracing response can also be observed, and recorded with FHRmonitoring starting at 5-5.30 am, to be intermittently observedthroughout the day, as needed. COT is switched to IOT if BPPS ismaintained at least as 6. Similar FHR monitoring during oxygen weaningcan be incorporated for CAT-4 management also, or at any time for anypatient for additional and immediate observation of fetal response toweaning, and for charting the same. While BPP is time taking needing thepresence of a physician or any specially trained professional, FHRobservation is easier, and is a familiar monitoring technique to all thecare-takers. Any non-reassuring tracing can be an indication toimmediately restart oxygen therapy, as a standing order. Such dailymonitoring needs to be continued until the patient is stabilized on aparticular DG₂₅₋₅₀ dose before discharge, with or without elected oxygentherapy. Any patient in this group or any other group if not stabilizedeven with continuous oxygen therapy that is tailored to the fetalresponse, it indicates at this point that there is significant impedanceto placental D-glucose transfer, probably due to placental vascularluminal obliteration, and transamniotic isotonic D-glucose supplementsare indicated as the last resort, which is discussed in detailsubsequently.

With the most distressed group being CAT-3 with BPPS of 4 or less onCOT, the patients of this group may need SIPP catheter placement fortransamniotic isotonic D-glucose supplements, if there is nosatisfactory improvement of score after 2-4 days of treatment with COT.

The Maternal IV Hypertonic 50% Glucose (DG 50) Treatments forGestational Ages 32 & (+) Weeks—

For BPPS of 8 or more (32, GROUP-A)—The protocol and management ofcomplications of this GROUP is the same as the previous group (that is26-31, GROUP-A) The group can be started with DG₅₀ for all BPP scores.If the fetus responded to treatments with out need for oxygen, and witha BPP score of 8 or more, the treatment is continued up to 34-35 weeksto plan delivery by checking L/S (lecithin/sphingomylin) ratio forneeded corticosteroid therapy. For planning delivery, along withbiweekly NST/BPP, biweekly Doppler velocimetry is also helpful.

For BPPS of 6 or less (32, GROUP-B)—the mother is hospitalized,immediately started on 6-8 L/minute of continuous oxygen therapy (COT).The AF is drawn for testing of L/S ratio, lactate/lactic acid levels,and immediate corticosteroid injection done. A maternal IV infusion ofall B-complex factors and minerals in maximal allowed doses is given.The effects of vitamin deficits on the most distressed fetuses arediscussed in the last section ‘The neonatal care of an IUGR baby’. Afterthe patient is stabilized on COT (which implies improvement of BPP scoreat least by 2 on COT), the preceeding algorithm protocol is followed(while the AF LA levels also are found in/brought to an acceptablerange), until the fetus acquires reasonable weight gain, with cesareandelivery planned at 34-35 weeks. The pregnancy not being remote fromterm, the management of this group is not laborious. Even 32 weeksneonates are more prone for morbidity/mortality compared to their AGAcounterparts, and hence allowing even few more weeks of intrauterinestay can be a saving measure.

Vascular access for glucose therapy—Once definitive fetal growth isobserved, the mother is a potential candidate for continued IV glucosetreatments. In view of at least 6 more weeks to pass, with prospectiveelective abdominal delivery soon after, a peripherally applied centralvenous catheter access has to be strongly contemplated, and performedbefore discharge, as this is the best time for such procedure. This isapplicable to all groups remote from term. Simpler and modifiedmaterials and methods for such peripheral venous access is describedlater. The possibility of not finding a vein after few days, and remotefrom the time of fetal viability can be anxiety provoking to thepatient, and to her care-takers as well. For patients not remote fromterm, and maintained on regular IV line, if the available veins areexhausted just around the time of fetal viability and before electivedelivery, subclavian triple lumen central line placement can be anoption for such patients.

Patient education, and maternal care by home health nurse—All thepatients need to be educated about the treatment, and the strict asepticmanner under which the intravenous access has to be conducted, for thepatients to continue the treatment at home. A home health nurse needs tobe assigned to monitor the patient, and to attend her at home, when everneeded.

The above hospitalization of the mother with bed rest/oxygen weaning, anaverage of 7 days or more, should be viewed as days less than those apremature/dysmature baby may otherwise have to spend in NICU (neonatalintensive care unit), but with unpredictable outcome, despite the traumainvariably inflicted to the neonate, even in it's most hospitable and anintensely caring new world.

The transamniotic isotonic glucose supplements, and the means ofamniotic cavity access, either diagnostic or therapeutic—Any patient ifnot stabilized even with continuous oxygen therapy (COT) that istitrated to the fetal response—it indicates that there is significantimpedance to D-glucose transfer probably due to placental vascularluminal obliteration, and transamniotic D-glucose supplements areindicated as the last resort (which is discussed in detailsubsequently), as unresolved hypoglycemia is certain. In addition, if AFlactic acid level is low or normal to start with and on COT, it clinchesthe diagnosis of ongoing fetal hypoglycemia (when seriousinfection/genetic fetal compromise is ruled out).

When the amniotic cavity access is one time, or more, the ‘sterile patchtechnique’ (devised by the author inventor) is strongly advised. Itinvolves placing any conventionally used antiseptic patch-like skincleaning device, like an ‘alcohol patch’ over the sterile skin puncturesite of the maternal abdomen, through which the needle is inserted,while care is observed for the center of the ‘sterile-patch’ to beuntouched by the injector's hand. The amniotic cavity is accessed underultrasound guidance to avoid the placental site, while the bladder iscompletely emptied, to avoid inadvertent bladder entry. Uterinecramping, vaginal spotting, or fever need to be watched for. AF leakoccurs in 1-2% of cases, but stops in 2-3 days. Consequentialmiscarriage is not common, as the amniotic membrane seals, and AFaccumulates (Marion S V et al). When there is question of whether or notAF was aspirated for the required testing, the crystalline arborizationtest can be used. Rh sensitization is possible and anti-D immunoglobulin(Rhogam) is indicated for Rh-negative susceptible mothers, even aftersingle amniotomy. As a general rule, a pool of AF can be accessed in themid suprapubic area (better by upward displacement of fetal head), incase the placenta is visualized to be located elsewhere, and in thissite, the separation of the recti reduces the intervening maternaltissue (Whitfeld C R, 1978), and the fetus is untouched by the needle.AF pocket can also be found by careful palpation, near the fetal limbs,or behind the fetal neck in case of breech.

Additional Comments on the Above Protocol—

1. When there is equivocal AF measurements lowering the BPP score—checkthe Umbilical artery S/D ratio. Patients with oligohydromnios but normalumbilical artery doppler S/D ratio are less likely to have poorperinatal outcome. With normal Umbilical artery S/D ratio, grade AFpocket measurements as score 2, hydrate the patient with 2-3 liters perday under bed rest, and reevaluate.2. If there is doubtful fetal breathing—when there is doubtful fetalbreathing with unequivocal score or lowering of the BPP score, checkumbilical venous Doppler for clarification. During fetal breathing, theumbilical venous waveforms are undulating, such wave forms correspondingto fetal inspirations, with a frequency much lower than fetal heartrate.3. Correlation of BPP with fetal blood pH—BPP score of 8-10 correspondsto fetal blood pH of 7.37 (in the normal range), and a score of 6corresponds to a pH of 7.33, and a score of 4 with pH of 7.28 (Manninget al).4. O₂ Therapy—The uterine placental vasculature during pregnancy isunique in that it is refractory to changes in blood gas tensions (PO₂and PCO₂). Therefore, oxygen therapy either due to maternal or fetalcauses will not cause placental vasoconstrictive response, and hencethere is no adverse effect on fetal blood flow. The fact that the oxygendemands are more for aerobic oxidation during peak blood glucose levelsand such demands can be less as the levels decline, and further, theprogressive alleviation of fetal hypoxia by 33+%, 400%, and 10% viadifferent metabolic consequences, as a multifaceted response due tomaternal D-glucose therapy—makes the oxygen deacclimatization taperingtolerable to the fetus.5. CO₂ production—Renewed glucose metabolism in the fetus can generateproportional amount of CO₂. In the glycolysis-citric acid cycle, for theaerobic combustion of 1 molecule of glucose, 6O₂ molecules are used, andalso 6 CO₂ molecules are liberated. That means, combined glucose-O₂utilization always generates CO₂ in direct proportion. However, maternalhyperoxygenation also facilitates Haldane effect at the placental level,that is, more of O₂ picked up by fetal hemoglobin also facilitates moreof CO₂ to be released from it, to enter the maternal compartment.Therefore, in the face of artificially and therapeutically improvedfetal oxygenation (but yet with the prevailing placental insufficiency),a resultant fetal hypercarbia (hypercapnia) may not be feared. TheHaldane effect can be considered as the body's evolutionary achievementas a cause and effect phenomenon in the case of life-sustainingdiffusion of vital gases, the O₂ vs. CO₂. That is, when oxygenationimproves, CO₂ that may also increase in direct proportion needs to belet out, also in the same proportion as the oxygen is increased.Continued Prenatal Monitoring of Fetal Well-being, and of Fetal GrowthParameters after the Patient is Discharged Home—1. Uterine height: is monitored every two weeks, as a measurement incentimeters.2. Fetal U/S: is monitored every two weeks, to affirm and documentongoing fetal growth.3. Fetal heart tracing: is monitored weekly, or earlier if motherreported suboptimal fetal movements.4. Maternal monitoring and documentation of fetal movements: it is donedaily, for 1 hour at a stretch. 10 fetal movements count in 1 hourduration is reassuring. If were found to be less, the mother shouldcontinue counting for one more hour. If they are fewer than 10 movementsin the 2 hour period, she should contact the physician. An alternate wayof fetal movement monitoring is, to count them for 30 minutes at astretch, 2-3 times daily. Normally, there should be at least 4 strongmovements during each 30 minute period. Encourage the patient tomaintain peaceful atmosphere at home, and to use a ring buzzer over theabdomen to startle the fetus from sleep before the 1 hour monitoring tomake the results more reliable. Both the self-administered glucosetreatments, and the fetal monitoring should be formally documented on asheet provided to her.5. BPP: it is monitored biweekly—after the patient is stabilized onoptimal DG₂₅₋₅₀ and sent home, and done earlier if mother reportedsuboptimal fetal movements.6. AF-LA and L/C ratio: normal or low levels indicate unresolved fetalhypoglycemia if patient is treatment-refractory, even on COT.7. UA and MCA velocimetry: it is monitored weekly—starting at 30 weeks,to plan or to be warned of the impeding need for fetal delivery, forpossible acute over chronic declining in the placental reserve, asexponential growth in the volume of placental terminal villi capillariesoccurs starting 31-36 weeks failure of which is reflected in Doppler FVWforms. The S/D ratio and PI are reliable parameters. One may not waitfor manifest ‘Absent End Diastolic flow Velocity’ (AEDV), or the‘Reversed End Diastolic flow Velocity’ (REDV).8. AF-L/S (lecithin/sphingomylin) ratio: it is done at 32 weeks.9. Umbilical venous Doppler: it is done any time for equivocal fetalbreathing off-setting the BPP score. It has to be noted thatnon-reassuring venous doppler signs are late signs, as fetal heartfailure and multi-organ damage are known to have already occurred, andhence not used as monitoring techniques of continued fetal well-being inthis protocol.

The Planning of Elective Fetal Delivery by Cesarean—

An IUGR baby with precarious placental reserve, or maintained onintermittent or continuous oxygen therapy (IOT or COT), is rarelyexpected to survive the stress of labor. On the other hand, mothers whoeither needed no oxygen or were successfully weaned of oxygen,persistently maintained 8-10 BPP score, did not manifest olgohydromnios,and had not demonstrated RDFV in umbilical doppler velocimetry—can betested with contraction stress test (CST) to estimate the placentalreserve. If found adequate, a vaginal delivery can be triedwith—continuous electronic fetal monitoring as the mother maintained on8 L/minute continuous oxygen therapy; continuous DG₅ IV fluids; the IVDG₅₀ as per the regular timings; the operating room kept ready foremergency cesarean. With all the time and effort spent in prolonging theintrauterine fetal stay for the delivery of a well grown baby with it'sbest potential preserved, when the time has arrived for it's delivery,swaying in favor of a cesarean is no doubt better.

Useful Decision Tools for Immediate Delivery of a Viable Fetus—

In planning immediate delivery, along with biweekly NST/BPP, weaklybi-weekly Doppler velocimetry is also helpful.

-   -   1. The Umbilical artery velocimetry (S/D ratio, PI, and        MCAPI:UAPI) is done weekly, starting 30 weeks (after the base        line study at the first encounter, for comparison), to be warned        of the possible acute over chronic declining in the placental        reserve. S/D ratio and PI are the useful monitoring parameters        and their abnormalities manifest 1-3 weeks earlier than        nonreactive NST, or falling of BPP score, for the physician to        be more watchful for the impeding delivery, as early as 34        weeks, and be prepared by finding the L/S ratio, if not done        already. Though Doppler velocimetry was disregarded on        admission, it's improvement with treatment, followed by        subsequent adverse changes are duly regarded for needed action        plan.    -   2. Reversal of brain sparing effect in the MCA-PI—it signifies        the failed fetal compensatory adaptation to a worsening uterine        habitat. Once observed, prolonging pregnancy is not a wise        choice. It is a strong indication for immediate delivery, after        a steroid injection, with or without AF-L/S results.    -   3. AF-L/S (lecithin/sphingomylin) ratio is done at 32 weeks, and        if not found to be more than 2, corticosteroid injection is        indicated. However, many IUGR babies are found to have L/S ratio        more than 2, even before 32 weeks, presumably due to the chronic        stress of inhospitable uterine habitat. The AF sphingomylin        concentration remains static through the later months of        gestation, but the terminal surge of the surfactant lecithin        (the dipalmitoyl lecithin) in the fetal lung is reflected        through the increased AF-L/S ratio. A ratio of 2 is associated        with respiratory distress syndrome (RDS) which is of higher        incidence in the neonates born before 32 weeks. The L/S ratio        of >2, yet associated with RDS is mostly seen with maternal DM        (Whitfield C R et al, 1974).    -   4. Helpful tools indicating fetal maturity when dates are        doubtful—(a) The Transcerebellar diameter (TCD) is valuable (as        in the nomogram by Goldstein et al, 1987,

TABLE 7 THE FETAL MONITORING/TREATMENT INTERVENTION TABLE PATIENT'SNAME: DOB: Diagnostics & interventions (the D: D: D: D: D: D: D: baseline data to be noted on day-1) day-1 day day day day day dayHypertonic/isotonic D-glucose therapy (specify strength/frequency) -                                   Uterine fundal height in cm (alsonote clinical oligohydromnios) -                                   Fetal ultrasound: note fetal weight & oligo- hydromnios (abnormal AF <2× 2 cm) -                                    UA: S/D ratio (≧2.6abnormal); PI (>2 SD abnormal) -                                    MCA:S/D ratio; PI - as a serial study (<5^(th) percentile abnormal) -                                   MCA-PI/UA-PI - serial recordings (ratio<1.08 abnormal) -                                    Ductus venosus flowvelocity wave form (the a-wave pattern) (not a routine) -                                   Umbilical vein flow velocity waveform (FVW) (not aroutine) -                                    Fetal heart:rate/variability/pattern -                                    Non stresstest (NST) -                                    Biophysical profile(BPP) Score -                                    Amniotic fluid lactate(AF-LA) level, or AF lactate/creatinine ratio (L/C ratio) -                                   Oxygen (O₂) therapy: intermittent (IOT) -continuous (COT) -                                    AF-LA level beforeO₂ therapy - AF-LA level after O₂ therapy - D—Date; UA—Umbilical artery;MCA—middle cerebral artery; S/D—systolic diastolic flow velocity ratio;PI—pulsality index.

TABLE 8 30 MINUTE BIOPHYSICAL PROFILE SCORE CHARTING; Patient'sname/DOB: Nonstress test Date Within 20 minutes of test Amniotic fluidFetal tone Preg. Reactive: score 2 Atleast 1 pocket size: Fetalbreathing Fetal movements Flexion/Extension weeks; Non-reactive: score 02 × 2 cm: score 2 ≧1: score 2 ≧3: score 2 F/E ≧ 1: score 2 total (withacoustic stimulation) <2 × 2 cm: score 0 absent: score 0 <3: score 0absent: score 0 score                                                                                                                                                                                                                                                                                                                                                         showing TCD in millimeters at 10^(th), 50^(th), and 90^(th) percentile)in an IUGR pregnancy, and it remains consistent throughout, independentof fetal IUGR.(b) Bony ossifications—the ossification of distal femoral epiphysisoccurs predictably around 32 weeks, and that of the proximal tibialepiphysis around 35 weeks, these two noted as prominent echoes distinctfrom the rest. Presence of distal femoral epiphysis of greater than 3mm, and the presence of any proximal tibial epiphysis indicate a maturelung in almost all IUGR fetuses (Galan H L, 2003).

The Procedural Description of the Vascular Access for the MaternalIntravenous Hypertonic D-Glucose Supplements—

A patient who responded to the therapeutic maternal hypertonic D-glucosetreatments, as indicated by definitive ultrasonic parameters of fetalgrowth response, but at a gestational age remote from term, needs asecure vascular access that tends to last for an average period of 2months. Broviac catheter that is a peripherally placed central venouscatheter is an ideal tool in this situation, as it can be managed by thepatient at home, without significant risk of sepsis.

The vascular access can be done via skin cut down in the anticubitalfossa, and with a venipuncture preferably through the brachial vein.Different pediatric sizes of Broviac central venous catheters areavailable, and the appropriate size can be chosen for this purpose. Thecatheter was originally designed for total parental nutrition (TPN) forwhich the placement of the catheter tip should be at one of the largercentral veins, and placement of the catheter tip as proximally aspossible is advisable for the hypertonic strength of D-glucose beinginfused. Smaller pediatric size Broviac catheter allows placement of thecatheter through the patient's forearm. Mentioning to the patient that ababy needle and a baby catheter are sufficient for the procedure insteadof the adult size (after making sure that the patient may notmisunderstand that it is for her baby in-utero) will reduce patientapprehension, and can improve patient-acceptance. However, it shouldalso be clarified that it is not a simple procedure like the regularperipheral venous access that people are mostly familiar with.

The Broviac catheter is made of soft radiopaque rubber, with a smallDacron felt cuff at a specified distance from the external end. Theinternal diameter is less than 1 mm for the pediatric sizes, and thecatheter consists of a thin walled intravascular segment and a thickwalled extravascular portion. The extravascular portion is tunneledthrough the subcutaneous tissue to a separate skin exit site, distantfrom the venotomy site. The Dacron cuff is so located in the catheterthat it will be positioned within the subcutaneous tunnel, and thefibrous tissue ingrowth into the cuff acts as an effective barrier tothe bacteria possibly migrating from the skin into the venous systemalong the outer surface of the catheter.

Technique of placement—Though typically the catheter is placed by venouscut down, it can also be placed in a manner similar to subclaviancentral venous access, using a guide-wire (the Seldinger technique). Thepatient's left forearm is chosen for a right handed person, so that thepatient can self-inject. As the chosen catheter entry site is theanticubital fossa (where the scar can merge with the ante-cubitalcrease), the catheter exit site can be somewhere on the medial aspect ofthe forearm, where it is less obvious, yet can be easily cared for, bythe patient.

To start with, an appropriate size pediatric subclavian central venousaccess kit should also be procured along with the pediatric Broviaccatheter. A small cut (of 1 cm) is made in the skin, over the proposedvenipuncture (venotomy) site. As the cubital veins are verysuperficially located, it is better to lift a skin fold, cut withscissors, and widen the skin incision to the desired length (avoidingthe scalpel contact with the superficial vessels throughout). From therea subcutaneous tunnel is made to the chosen skin exit site on the medialaspect of the forearm. When the tunneling instrument approaches the skinexit site, a small incision, about 1 cm, is made at the skin exit site.The tunneling instrument at it's exit picks up the catheter tip to bebrought to the venotomy site, while retreating in it's course. Then thebrachial vein is entered through the needle supplied in the triple lumenkit. The brachial vein can be seen or located by brachial arterypalpation. Using a guide wire and a vein dilator, the Broviac cathetertip is threaded into the vein through the guide wire, in a similarmanner that a subclavian central vein catheter is placed, as in theSeldinger technique. The catheter is passed into one of the centralveins or their largest distal veins to a distance that allows the Dacroncuff to be positioned in the patient's forearm inside the subcutaneoustunnel. The venotomy site incision is closed, and the catheter is fixedto the skin exit site by mono-filament nylon that is removed after 1-2weeks by which time fibrous ingrowth into the Dacron cuff has takenplace. Sterile povidone iodine ointment and a sterile dressing areapplied to the exit site, and the catheter is filled with heparintreated saline, and closed with hep-lock. The loop of the redundantcatheter if any is taped to the medial aspect of the forearm.

The patient has to be advised that even the hep-lock needs to be cleanedwith a povidone iodine ointment, and after use, covered with steriletape seal, so that the hep-lock is kept clean, what ever be thepatient's activity. The hep-lock has to be injected with sterile glovedhand through any sterile skin patch, like an alcohol patch, placed overthe hep-lock. The hep-lock is changed more frequently in view of thelong catheter in-dwelling time, and hence needed stringent care. Theextracutaneous redundant part of the catheter is also cleaned with theointment, and taped to the hand by sterile adhesive dressing. Theprocedure being least traumatic and least invasive, it is easy to gainpatient acceptance, as it is essentially like any simple peripheralvenous catheter placement, with least injury to the vessel wall, and inaddition, with a devised protection against sepsis, for the neededindwelling time. Ideally, the catheter placement is done in thecontrolled environment of an operating room, under aseptic precautions.

If the physician has not found any suitable tunneling instrument in thearmamentarium of the available surgical tools, to use in the smallcurvilinear confines of the fore arm, as aesthetics are also essentialin an exposed anatomical site like the fore arm of an young female, theauthor inventor of this writing advocates to use a Hegar cervicaldilator (or a Hank cervical dilator) for this purpose. It's smooth anddelicate curvilinear sigmoid shaped structure suits the contour of thefore arm, with the smallest size having 21 cm length, and 3-4 mmdiameter (half of the dilator is 3 mm diameter, whereas the other halfhas 4 mm diameter) (Gynex), and rough manipulations invariable withother instruments in this area, can be avoided. It can also make theneeded incisions to a minimum size. However, the procedure needs somemodification (as in Sumathi Paturu's subcutaneous tunneling techniquefor venotomy). It can be done in the following manner, using also astraight urinary catheter as a passage sheath.

Sumathi Paturu's subcutaneous tunneling technique for venotomy—To startwith, the sterile Hegar dilator is passed into a suitable size sterilestraight rubber urinary catheter, and so enclosed, the catheter tip canbe negotiated through the venotomy incision site to the skin exit sitelocated distally on the medial aspect of the fore arm. Following theexit of the tunneled instruments at the distal skin exit site, theinstruments can be gently moved side to side (not rotated on theiraxis), so that a wider and suitable caliber subcutaneous tunnel iscreated, as it needs to accommodate the Dacron cuff. Soon after, theHegar dilator can be removed retreating through the venotomy site,leaving the sheath of urinary catheter in place in the subcutaneoustunnel. The urinary catheter tip can be cut to expose it's whole caliberat the skin exit site. From this widened cut end, the tip of theBroviac's catheter can be passed to reach the venotomy site in theanticubital area. After the exit of the tip of the Broviac's catheterfrom the urinary catheter end, the urinary catheter can be removed overthe Broviac's catheter, which it had enveloped. It is done from thevenotomy site. It can be noted that only the tip and the proximal lengthof the Broviac's catheter has to pass through the urinary catheter. Ifthe creation of the tunnel poses a problem, a curved hemostat or curvedscissors can be used to separate the tissues, and to create the neededcleavage in the subcutaneous planes, but approached from both ends ofthe tunnel separately, as one straight plunge can make a curvilinearnegotiation difficult, as only the tip of these instruments is curvedfor a confined length. In a very lean person, or if the exit site ischosen on the anterior aspect of the fore arm, the tunnel can berelatively straight, and most of the instruments are suitable in thissituation though a hinge in an instrument always makes it wider, and cannever be as the ideal small caliber of a Hegar/Hank dilator.

The size of the urinary catheter is chosen in such a manner that it'smovement over the Hegar dilator is easy, but the fit not too loose.Leaving the tip as it is, the catheter can be cut at the other end tostart with, to use only the needed length for this purpose, that is, 1-2inches longer than the curvilinear length of the proposed subcutaneoustunnel. This procedure is suitable for any subcutaneous instrumentaltunneling and venotomy, for any regular catheter or for anyport-catheter placement, in any preferred venotomy site.

Further precautions that can be observed to prevent infection of thecatheter is—antibiotic lock technique, that was used successfully in themedical field, to treat and prevent central venous catheter infections.The technique involves injecting an antibiotic solution (preferablyVancomycin 2 mg/ml) into the catheter lumen, and allowing the antibioticto sit in the line for at least 12 hours, before surgically inserting itinto the patient. The catheter is periodically reinjected and theantibiotic is made to sit in a similar manner, after clamping thecatheter at the skin entry site. It has to be done after completelyemptying the blood column from the redundant catheter by antibioticinjection, before clamping the catheter at the skin entry site, andallowing the antibiotic solution to stand in the redundant catheterlumen until the time of the next D-glucose injection. It prevents thepossible infection introduced into the interior of the catheter lumenduring the daily use, which the Dacron cuff may not prevent. Vancomycin,like penicillin, is pregnancy category-B.

The Transamniotic Isotonic D-Glucose Fetal Supplements

The biochemical benefits attributable to normoglycemic status of thefetus, possibly achieved by the additional modality of the transamnioticisotonic D-glucose (DG₅ isotonic, or D₅ water) treatment is similar towhat was elaborately discussed under the section of ‘Maternalintravenous hypertonic D-glucose supplements’. However, being aninvasive procedure, though minor in nature, it is advised as the lastmodality of treatment when all else fails, including the concomitantcontinuous oxygen therapy (COT) with the maternal IV hypertonicD-glucose treatments. No improvement of BPP score during increments ofmaternal D-glucose therapy while on COT clinches the diagnosis ofongoing fetal hypoglycemia due to severe placental impedance. Thetransamniotic D-glucose supplements being not therapeuticallyall-inclusive in relieving the fetal growth restriction, the placentalsupplies of D-glucose through maternal treatment should be ongoing, andparamount. Normally the placental glucose requirements are more than thefetal, as the placenta extracts 50-60% of glucose entering maternalsinusoids for it's multitude of functional requirements, the mostimportant being supplying glucose to the fetus in the form of lactate,when transfer of D-glucose from the maternal compartment itself is low,as during maternal sleep cycles/maternal fasting.

Despite a last resort, nutritional supplements via amniotic fluid (AF)is scientifically an attractive proposition. The phenomenon ofintrauterine fetal swallowing is taken advantage of in this modality oftreatment. 5% of isotonic D-glucose solution can be safely instilledinto the amniotic cavity without adversely affecting osmotic forces. 5%D-glucose which is isotonic with maternal extracellular fluids should beisotonic with the AF, because the normal osmolality of the maternalplasma and the fetal plasma are in the range of 260-275 mosm, and soalso is the osmolality of AF from 20-30 weeks. Instillation of 100 cc of5% D-glucose twice daily is a supplementation of 10 G. of glucose thatwould amount to 41 kilocalories of energy supplement to the fetus, andit can be administered thrice daily (62 kilocalories) or four timesdaily, as the pregnancy advances. Even if AF is replaced every 3 hours,still substantial amounts can get into the fetal body.

Studies of transamniotic fetal feeding (TAFF) of pregnant rabbit modelswere conducted by Mulvihill et al in 1985 using 10% dextrose solutionwhich had been associated with increase in fetal weight. However,studies of Flake et al with solutions of dextrose, amino acids, and oflipids, either alone or in combination did not reverse growthrestriction in the natural runt rabbit fetus. The reasons for thesecontroversial results can only be postulated. Too much of dextrosewithout required vitamins (especially of the B-complex factors likethiamine) needed as cofactors for the carbohydrate metabolism (presumingthat the rabbit's biochemistry is similar to human) could beoverwhelming to the fetus. Too much of lipid or of amino acidsupplements with or without glucose can be a stress to the oxidativemachinery of the fetus, the beta oxidation of fats, and the amino acidcatabolism for energy-yielding purposes being oxygen/ATP consumingpath-ways. It can make the existing hypoxia worse, and theco-administration of glucose not very beneficial. The concomitantmaternal treatments that include prior IV supplements ofvitamins/minerals, and also the IUGR diet with maximal daily supplementsof vitamins, minerals, and of trace elements will compliment and makethe transamniotic fetal treatments fulfilling, as the maternal routeappropriately relies upon treating the fetoplacental unit as a whole.The AF 5% D-glucose supplements further improve voluntary fetalswallowing because of the improved taste, as in the research studies anew born seemed very discriminative in preferring oral sugar solutions(Johnson P & Salisbury D M).

TABLE 9 The amniotic fluid composition during normal pregnancy AFconstituents 16 weeks 34-36 weeks Author Osmolality 275  265 withcontinued Whitfield CR (mosm/L) decrease to term Sodium 136  132 withcontinued Whitfield CR (mEq/L) decrease to term Total Protein 4.0  3.0with continued Whitfield CR (g/L) decrease to term Urea 2.8  3.8 withcontinued Whitfield CR (mmol/L) decrease to term Creatinine 49  149 withcontinued Whitfield CR (mg/L) increase to term Lecithin 20 30-100 withWhitfield CR (mg/L) terminal increase Total lipids 480 mg/L Gadd L Fattyacids 240 mg/L Gadd L Glucose at lower concentration than, but Gadd Lproportional to maternal serum level Amino acids found in sameconcentrations as in Gadd L the maternal plasma Chloride, K⁺, resemblethe concentrations of Gadd L Ca²⁺, Mg²⁺ and maternal extracellular fluidphosphate CO2 high Gadd L PCO2 - 57 mm/Hg Rooth et al (1961) Lactate/less than 10.1 mmol/L Pardi et al (1987) lactic acid

The AF contains the valuable constituents as shown in the table-9 thathad been proved to be essential for optimal fetal growth.

As the daily puncturing of amniotic sac is replete with dangerous sepsisfor the needed duration of the treatment involved in human pregnancy,the invention contemplates to achieve such daily transamniotic accessthrough a Subcutaneously Implanted Pregnancy Port Catheter (SIPPcatheter) placement accomplished through a minimally invasiveextraperitoneal (from outside of the peritoneum) suprapubic amniotomy.There is least danger of infection, and great ease of daily use, afterit's one time insertion.

The novel transamniotic insertion of the Subcutaneously ImplantedPregnancy Port with catheter (SIPP catheter)—The novel procedure of theextraperitoneal suprapubic transamniotic port-catheter placement istailored for obstetric purposes, and is devised by the author inventor,while the subcutaneously implantable (intravenous) catheter with portwas originally devised decades ago by past inventors for exclusive usethrough the intravenous route. The catheter part of the device of theinstant specification is also modified by the author inventor to besuitable for transamniotic approach of the amniotic cavity, and is alsoconfigured to relieve malfunctions unique to the milieu. The port,however mostly retaining it's original structure as was devised, can beused safely through the long duration of pregnancy, encompassing a‘sterile-patch technique’, also devised by the author inventor, to makeit's use sepsis-free, the introduction of infection into the amnioticcavity being a much feared complication inherent to countless number ofport punctures involved.

The sterile patch technique for transamniotic infusion of isotonicD-glucose—as was described in an earlier section, it involves placing onthe well cleaned (port) puncture site of the maternal abdomen, anyantiseptic patch-like skin cleaning device, like an ‘alcohol patch’,without touching the center of the patch, through which the amnioticcavity can be accessed using a straight needle. The corners of the patchcan also be carefully taped for a stable placement.

The access site of the amniotic cavity, for the extraperitonealtransamniotic SIP port catheter placement—As a general rule, a pool ofAF can be accessed in the mid suprapubic area (by upward displacement offetal head), in case the placenta is visualized to be located elsewhere.The separation of the recti reduces the intervening maternal tissue(Whitfield C R, 1978), and it virtually eliminates fetal injury, as thefetal body as a whole is out of reach. If the mother is kept inTrendelenburg's posture for few minutes, it also allows the cord tosettle in the upper uterine pole, when the mother can be brought back tothe supine position, with a slight leftward tilt for surgery.

The Structural and Functional Description of the SubcutaneouslyImplanted Pregnancy Port (SIPP) with Catheter—

The diagrams used to illustrate the design of the SIP port with catheterare not necessarily drawn to scale, and are shown in FIG. 10 and in FIG.11.

The SIP port and the catheter—The SIP port is devised as asubcutaneously implantable port (200) with a housing reservoir body(201) containing a dome or diaphragm shaped septum (202) (FIG. 10). Theseptum (202) is made of implantable medical grade rubber, a siliconeelastomer. The dome (202) is capable of being punctured by a needle (aHuber needle is conventionally used, but regular needle is intended fortransamniotic use), and is capable of resealing upon removal. Thereservoir body (201) is conventionally made of a wide variety ofmaterials like titanium, steel, ceramic, or plastic. For obstetricpurposes, to be used for a relatively shorter duration, a medical gradeplastic can be chosen. It makes the housing reservoir (200) light weightto be well stabilized without down-sliding over the enlarging convexityof the maternal abdomen during pregnancy. The dome septum (202) can beas small as 2 centimeter diameter for this purpose, but bigger sizes arenot precluded. The largest dimension of the port (200) itself is about2.5 cm. The bottom or under surface of the body frame of the housingreservoir (201) is contoured as concave shaped, to sit with wellapproximation over the convex contour of the maternal abdomen. Thereservoir body (201) is also expanded as a flat plate of 0.3 cm width init's perimeter (206). The silicone dome (202) is configured assemispherical in contour, the most stable shape for the intendedfunction, whatever be the shape of the reservoir body (201). Theperimeter (206) flat plate of the port reservoir body (201) has threeapertures (234) placed equidistant in the three quadrants of the port(200), so as to secure the port in it's subcutaneous port pocket bysuture ligature with any preferred non-absorbable material.

The reservoir body (201) is connected to a catheter (208) in thequadrant devoid of aperture, through a port stem or segment (210), and alocking collar (203). The stem or segment (210) that couples the port(200) and the catheter (208) is made of similar material as the catheter(208), whereas the locking collar (203), devised as an extension of theport (200), is made of a similar material as the port body (201) itself.The catheter (208) is made of polyurethane, with an internal diameter of0.89 mm, and a length ranging 50-70 cm, though higher dimensions are notprecluded. It's intrauterine portion is thin, and the rest, especiallythe extrapelvic portion is thicker in the substance thickness of it'swalls. Maternal abdominal dimension vary widely. Hence a wide range oflengths are devised to be available. The length further accommodates forthe fluctuating size of the bladder, and for the enlarging size of theuterus through pregnancy. The SIPP catheter has a distinct distal endand a distinct proximal end that are further described as follows—

The distal end of the catheter—The port unit (200) connected to thecatheter (208) through port stem or segment (210) is actually a smalloff-shoot of the catheter (208) from it's distal end (214), as shown inthe FIG. 10.

The catheter (208) distal to the port segment (210) has a length of 2-3cm that is configured as a distal segment (220) of the catheter, with adetachable silicone rubber trumpet-like terminal (222) 1 cm in it'slargest diameter (with plastic underlay except under the terminal flatsheet), and structured like a hep-lock device capable to be puncturedwith a 18-19 gauge needle, as a means of passing a guide-wire throughthe catheter length. Said guide-wire is passed into the catheter lumento relieve any block (by the amniotic fluid solid components), notrelieved by infusions through the catheter, of the isotonic D-glucosewith the force of a bolus. The guide-wire used for the purpose ofinserting the catheter (208) initially is saved, autoclaved, and usedfor this purpose, if necessary. An additional trumpet (222) is suppliedin the set, in case the trumpet leaks, due to punctures involving an 18gauze needle. Such leaks can be identified by a local swelling. Thedistal trumpet segment (220) and the detachable trumpet (222) configuredto be the direct continuation of the catheter lumen, enable theguide-wire's passage easy and uninterrupted. The trumpet (222) jointwith the trumpet segment (220) is a tight threaded coupling thatprevents dislodgement of the connection. As the extrauterine catheter(208), especially the distal end (214) being much thicker with asubstantially larger lumen also, blockage by amniotic fluid particulatematter is not an occurrence in the distal catheter (214), including thetrumpet segment (220), and the port segment (210).

The proximal end of the catheter and the catheter cuff—The proximal part(236) of the catheter (208) is shown in FIG. 11. It's terminal has asmall hole (232) that communicates with a fluid cavity, which is theamniotic cavity fluid pocket (136). The proximal part (236) of thecatheter (208) has a butterfly-like winged polyurethane attachablestabilizer (224) having a central cuff (226) with a slit through it'saxial length that can be opened to envelope the circumference of theproximal segment (236), and to be positioned immediately outside theuterine wall soon after the amniotomy catheter insertion. The cuff (226)is short in it's axial length, only 2-3 mm. It's two wings (228) havecentrally placed marginal apertures (230) to be sutured in place to thesuperficial layers of the myometrium, with a non-absorbable suturematerial, whereas the inside of the cuff (226) is glued to the exteriorof the proximal catheter (236) with biocompatible glue, so that theintrauterine part of the catheter (236) remains fixed and stable throughpregnancy.

The accessory parts—The SIP port and catheter set has accessory partsintegral to the function of it's insertion, in a manner that arerequired of the conventional Seldinger's vascular access technique,except that it is done through the uterine puncture site instead of avenotomy site of the conventional procedure. The accessories include apuncture dilator (similar to a vein dilator) with 0.89 mm of internaldiameter, and a guide-wire made of steel having 0.64 mm diameter, and alength ranging 55-75 cm. The guide-wire is made in the conventionalmanner, comprising of helical wire coils over a core of straight solidwire, with a good column strength, and can be easily bent in a mannerneeded for the purpose of catheter insertion. The set uses regularneedle, size 18-19, but the needle is longer (8-10 cm length), similarto a spinal needle.

The Surgical Technique of the Placement of the Subcutaneously ImplantedPregnancy Port (SIPP) Catheter with Emphasis on the Related PelvicAnatomy—

The anatomical description of the pelvis is invariable to understand thesurgical procedure for the suprapubic transamniotic placement of theextraperitonelly inserted SIP port. The pelvic anatomy in the ensuingdescription is what is normally encountered in the non-pregnant female,and is so preserved through pregnancy.

The structural description of the pelvis-abdomen and the subsequentnarration of the surgical procedure are done in the anatomical position,the conventional manner. All the drawings are illustrated in erect rightsagittal/median view to relate/orient unambiguously to the organdescriptions narrated in the conventional erect anatomical position.This refers to a surgical illustration also (FIG. 9), though a supineposition is conventionally used for most of the abdominal/supra-pubicsurgeries, including that described in the specification.

The Normal Anatomy of the Pelvic Organs—

As seen in the FIG. 7, in the human pregnant female, for the SIP portcatheter placement via the suprapubic approach, the major organencountered is the urinary bladder (102) that is located anterior to theuterus (100) and posterior to the pubic symphysis (101). The urinarybladder (102) is a hollow organ that receives urine, and empties itintermittently on volition. The changeable anatomical milieu as thebladder fills can be taken advantage of, as it is the aim of thissurgical procedure to place the SIPP catheter through an extraperitonialsuprapubic route, as it's redundant pelvic course can otherwise make theloops of small intestines (104) get entangled/trapped during earlypregnancy, when there is enough room in the pelvis (106) and abdomen(108) for such event to happen, causing bowel ischemia and gangrene.Anterior to the uterus (100), the urinary bladder (102) lies immediatelybelow the pelvic peritoneum (110), and when empty, the bladder ispositioned wholly within the pelvis (106). As it fills with urine, it'sneck (112) and lower part remain stationary, while the upper part (114)balloons up (FIG. 8) lifting up the peritoneum (116) off the anteriorwall (118) of the lower abdomen (108) (reference—Cunningham's manual ofpractical anatomy, 12^(th) edition, volume-2, Thorax and Abdomen, page452, 1962, Oxford university press) and in this situation the uterus canbe reached extraperitoneally in this surgical procedure, through anincision (122) made supra-publically, for the placement of the SIP portcatheter (208).

Sumathi Paturu's Technique of Extraperitoneal Suprapubic Pelvic/UterineApproach and Amniotomy Through SIP Port Catheter, Also Involving SumathiPaturu's Subcutaneous Tunneling Technique for a Remote Port Placement—

The surgical procedure for the placement of the SIPP catheter is plannedas elective surgery. The placental position is confirmed to be in theupper uterine segment prior to surgery. The patient will be started onIV D₅ W at 84 ml/hour, and inserted with an indwelling Folley's catheterthe night before. The Folley's catheter end is clamped and taped to thepatient's thigh facilitating the catheter bulb to remain in positionoccluding the internal urethral meatus, so that the bladder distends toabout 4-5 cm above the pubic symphysis. The patient rests in leftlateral position, and is mildly sedated to blunt her discomfort.

For the surgery, the patient is made to lie in a supine position with aslight left lateral tilt, maintained throughout. In a right handedpatient, the SIP port is placed over the right side of the abdominalwall, so that the patient will be able to self-inject. An area justmedial to the right anterior superior iliac spine is a suitable site tocreate the port-pocket, as it's distension during pregnancy is minimalso that the port will be stable in it's position. As the largestdimension of the port is about 2.5 cm in diameter, a skin incision aboutthat size is appropriate to insert the port into it's subcutaneous portpocket (hence forth called as port site). To start with, a 1 cm incisionis made at the port site. To create a sub-cutaneous tunnel, a suitablesize Hank cervical dilator available in 19.2-26.9 cm length range(Gynex), and a wide variety of small diameter sizes is used. It issigmoid shaped with a smooth curvilinear configuration that can beeasily negotiated over the convexity of the maternal abdomen. To startwith, a preferred small diameter size Hank dilator is ensheathed in asuitable sized straight urinary catheter that allows free movement ofthe dilator within the rubber sheath. The ensheathed Hank dilator thenis inserted through the 1 cm skin incision at the port site, and passedthrough the subcutaneous plane of the lower anterior abdominal wall, tocourse towards the pubic symphysis (hence forth the symphysis site). Asharp scissors can be used at the port site to create a plane ofcleavage in the subcutaneous tissues.

A 2.5 cm (1 inch) transverse suprapubic incision (122, FIG. 9) is madein a manner similar to a Pfannenstiel incision, and the subcutaneous fatis cut and separated in all directions as much as possible from thesuperficial rectus sheath, and the sheathed Hank dilator is brought outthrough this incision of symphysis site. The Hank dilator is removedfrom it's envelope sheath of straight urinary catheter through thesymphysis-site by cutting the tip of the catheter to expose it's wholelumen. Alternately, it can be removed from the port site also. The SIPcatheter tip (236) is then introduced through the end of the straighturinary catheter at the port-site, and is brought to the other end atthe symphysis site. Then the straight urinary catheter is removedthrough the symphysis site, over the SIPP catheter it had ensheathed, sothat the SIP catheter is left in the subcutaneous tunnel.

If the maneuver is difficult, the course of the tunneling Hank cervicaldilator sheathed in the urinary catheter (and later the SIPP catheteralso sheathed in the urinary catheter), can be interrupted in the midway(at the mid-inguinal area), and brought out through a small skinincision, to repeat similar procedure as started at the port-site, forthe tunneling instruments to reach the symphysis destination.

The 2.5 cm skin incision (122) at the symphysis site can be extended to4-5 cm if necessary in case of an obese abdomen. The exposed rectussheath is cut vertically as much as possible, when it may be noted thatthe peritoneum of the lower abdominal wall is not encountered, andfurther more, the distended and bare upper part of the bladder (114),also devoid of the peritoneal covering (116) is immediately underlyingthe cut rectus sheath (FIG. 8). The peritoneum (116) of the anteriorabdominal wall (118) is not visualized, because it is lifted up alongwith the distended upper part of the bladder (114), peeled away from thelower anterior abdominal wall (118). The incision of the rectus sheathis made very carefully by always picking up a fold of the sheath, sothat the distended bladder underneath is not accidentally injured. Atthis point, a small size L shaped retractor (120) is inserted throughthe incision (122) in such a manner that the limb of the retractor (120)traverses vertically up anterior to the bladder (114), and behind theanterior abdominal wall (118) until it reaches the undersurface of theperitoneal shelf (124) that overlies the upper part of the bladder(114). Ultrasound guidance is helpful to delineate the anatomicaldistinctions of this area. At this time, the bladder is allowed to emptyvery gradually, as the retractor (120) blade is moved down much slowerthan the bladder (114) that is receding towards the pelvis (106). As theretractor blade (120) is moving down, it's vertical position isgradually changed few degrees towards horizontal position each time, sothat when the bladder (114) almost reaches pelvic position, theretractor blade (120) assumes a totally horizontal position that keepsthe peritoneal shelf (124) above it (FIG. 9). As the superior surface ofthe receeding bladder (114) is visualized at the incision (122) level,it's emptying is put on hold, and the peritoneum is gently separatedfrom it's superior surface as far as possible. The bladder (102) is nowallowed to empty slowly, also separating the peritoneum if any, over it.At this time, the lower uterine segment (128) devoid of peritonealcovering comes into view.

The fetal head (130)/the presenting part is displaced upward, and heldin that position by an assistant. The patient can also be kept inTrendelenburg's position, if loops of the umbilical cord (132) arevisualized at the lower uterine pole (as seen through the ultrasoundequipment), so that they will settle towards the opposite pole. Thepatient is then slowly put back to horizontal position, with the fetalhead (130) still held up by an assistant. The 18-19 gauze amniotomyneedle provided in the SIPP catheter kit, along with a syringe (134) isnow inserted to traverse through the lower uterine segment (128) toreach the amniotic fluid pocket (136) below the fetal presenting part.Clear white amniotic fluid fills the syringe (134). The 18-19 gaugeneedle can be moved gently in a wider circular motion to dilate theuterine puncture site (allowing more of myometrial, and less of amnionpuncture to dilate), which maneuver is better than introducing anotherinstrument like a puncture dilator which can widen the amniotic membranepuncture with the chance of amniotic fluid leak at this site. The amnionbeing a delicate membrane, it can easily yield to the passage of thesoft SIPP catheter over a guide-wire, and hence minimal instrumentalmaneuvers through it are better. At this time, the guide-wire providedin the SIPP kit is introduced into the amniotic cavity through theneedle, and after sufficient length of the guide-wire is in the amnioticcavity, the needle over it is removed. Following it, the distal end ofthe guide-wire is passed through the proximal part (236) of the SIPPcatheter (208) that was already brought to the amnitomy site. As most ofthe catheter (208) in this situation is not free, and is located in thesubcutaneous plane, it is the passage of the guide-wire into thecatheter (208)(and not vice versa) that needs to be accomplished untilthe guide-wire is felt at the distal trumpet segment (220) that isopened now by disarticulating the trumpet (222) to let out theguide-wire, when also the SIPP catheter (236) tip is passed into theamniotic cavity over the guide-wire, as the let out trumpet end of theguide-wire is secured by hand. Following it, with sufficient length ofthe catheter (236) within the lower uterine segment, the guide-wire iscompletely let out through the opening of the trumpet segment (220) in aswift motion (while the catheter entry into the uterus is alsosteadied), and the trumpet (222) is quickly articulated with it'strumpet segment (220), not to allow too much of amniotic fluid leak. Thetrumpet segment (220) being configured as the direct continuation of thelinear length of the catheter, the guide wire's exit is made easier anduninterrupted from this route. The amniotic cavity can be immediatelyinjected with 50-100 cc or more of isotonic 5% dextrose, to replace thelost volume.

A 5-10 cm of intrauterine length of the SIPP catheter (236) is required.A red mark on the proximal catheter (236) delineates this length. Thecuff (226) of the catheter stabilizer (224) is encircled around theproximal SIPP catheter (236) out side this red mark, and is secured(glued) to the SIPP catheter exterior with a biocompatible adhesive(epoxyamine or the like). The apertures (230) of both the cuff wings(228) are sutured to the superficial muscular layers of the loweruterine segment (128) so that the catheter will not be dislodged, northe intraamniotc catheter (236) length lowered. The retractor (120)keeping the peritoneal shelf (124) away from the bladder (102) is nowremoved to let the peritoneum (124) fall back to it's position in thepelvis (106). About 10-15 cm of redundant length of the SIPP catheter(208) within the extraperitoneal pelvic space is sufficient to allow forthe uterine rise and the bladder distention. The incision (122) isclosed in layers, while allowing the SIPP catheter (208) to stay in thesubcutaneous and extraperitoneal planes, traversing from the port-siteto the amniotomy site.

If the Lower Uterine Segment Devoid of Peritoneum is not Visualized—

If the lower uterine segment (128) devoid of peritoneum is notvisualized, it indicates that the posterior utero-vesicle fold ofperitoneum is still attached low down to the lower uterine segment (128)when one may see two layers of the peritoneum covering the lower uterinesegment (128), as the peritoneum is separated from the superior surfaceof the bladder (114) through the incision (122). The anterior foldrepresents the peritoneum separated from the superior surface of thebladder (114), whereas the posterior fold is the posterior part of theuterovesical fold of peritoneum, the peritoneum that normally covers thelower uterine segment (128). If such situation is encountered, make asmall transverse incision 1-2 cm size over both the peritoneal layers,pass a suitable size straight urinary catheter between the myometrialwall of the lower uterine segment (128) and the posterior fold of thecut peritoneum, and let the urinary catheter be maneuvered down to reachthe uterovesical junction. This can be accomplished by rolling and/orside to side movement of the urinary catheter with a tip sufficientlytough for this maneuver. The straight urinary catheter is picked up justanterior to the reflection of the uterovesical fold of peritoneum, thisstep also aided by finger guidance of the surgeon. If visualization isneeded, a culdoscope is a suitable instrument in this narrow retropubicspace. The proximal end (236) of the SIPP catheter (208) (brought to thesymphysis site earlier) can then be introduced through the urinarycatheter tip that is cut and widened, so that the proximal SIPP catheter(236) can reach the lower uterine segment (128) retroperitoneally,passing through the urinary catheter that ensheathed it. It is broughtout through the cut peritoneal opening emerging from the urinarycatheter, when the urinary catheter itself is removed retreating it'scourse over the SIPP catheter (236). Now the proximal SIPP catheter(236) is introduced into the amniotic cavity by amniotomy in a mannersimilar to the above described technique, using a 18-19 gauge needle,and a guide-wire.

After the cuff (226) of the attachable stabilizer (224) is glued to theproximal SIPP catheter (236) and the wings (228) sutured to themyometrium with non-absorbable sutures, both the layers of the cutperitoneum are sutured separately with an absorbable catgut, theposterior layer sutured first, and then the anterior layer. Followingit, the retractor (120) holding the peritoneum (124) is removed. Now theSIPP catheter (208) is located completely extraperitoneally within thepelvis (106). Leaving sufficient redundant catheter (208) length of10-15 cm within the extraperitoneal pelvis (106), the incision (122) isclosed in layers.

Soon after the completion of the procedure at the amniotomy site, theport-site incision is extended to 2.5 cm size, and the distal SIPPcatheter (214) structures, the trumpet (222), and the port (200) areinserted into port-pocket, and the port (200) sutured to the tissueswith a non-absorbable material passed through the three apertures (234)of the port (200).

An Alternative Technique—

If the uterus can not be approached interiorly, it can be approachedobliquely at an angle 45 degrees from the midline sagittal plane. Whenthe bladder is distended, the uterus is peeled off it's peritonealcovering over some area on it's anterolateral surface, due to someseparation of the anterior fold of the broad ligament. Ultrasoundguidance is absolutely essential for targeted entry of the needle.Giving the patient pyridium before surgery can make the urine colororange, and the previously emptied urine can be saved to refill thebladder again during this tangential uterine approach. If entry into theamniotic cavity is confirmed through a percutaneously inserted 18 gauzeneedle, a guide-wire is introduced, and the needle removed. Followingthe guide-wire track, the uterus is approached through a small incisionin the anteriorolateral abdominal wall (similar to a Grid ironincision). If the bare area of the uterus is not delineated, there canbe two layers of peritoneum anteriolaterally, just as it was encounteredthrough suprapubic approach. The bladder can also be distended more towiden the bare area of the uterus. As the pelvic floor is roomy, it iseasier to reach lower uterine segment using a straight urinary catheter,as was done in the suprapubic approach, also using culdoscope ifnecessary, followed by transamniotic SIPP catheter insertion over theguide wire. The proximal SIPP catheter (236) is brought to this sitefrom the symphysis-site traversing the subcutaneous plane.

The antepartum and intrapartum management of the patient treated withD-glucose transamniotic supplements are similar to what was alreadydescribed under the section of maternal IV hypertonic D-glucosetreatments, as this is only an additional treatment to the on-goingmaternal IV D-glucose supplements. CAT-3 with BPPS 4, on 6 L ofcontinuous O₂ therapy (COT) is the most distressed group of thealgorithmic protocol, and the score showing no improvement in 2-4 daysis the end point at which placement of the SIPP catheter iscontemplated. An elective Cesarean section, as soon as the fetus isviable is indicated, when the SIPP catheter is removed from it's uterineattachment, and the port removed from it's subcutaneous port pocket.

Neonatal Care of an IUGR Baby

The anaerobic metabolism of glucose secondary to chronic hypoxic insultsif becomes significant in fetal IUGR, lactic acidemia can progressivelythreaten the fetal existence in-utero. Huang et al (1999) and Rishi KantO et al (2006) conducted studies of normal neonates, and those whosustained acute/chronic perinatal insults of hypoxia/asphyxia as fetusneonates, with resultant neonatal Hypoxic Ischaemic Encephalopathy(HIE). They studied the very first urine samples excreted within 6 hoursafter birth that presumably reflected the blood/urine chemistry afterthe hypoxic insult had resulted. Though creatinine excretion depends onglomerular filtration rate, and is reduced during fetalhypoxia/asphyxia, lactate continues to be excreted, with it's levelreflecting in the AF that is mostly composed of fetal urine (Rishi Kantet al).

The most recent and the only study of it's kind was done in Netherlandsby Torrance H et al that involved AF lactate measurements, as areflection of fetal hypoxia. This study measured AF lactate creatinineratio (L/C ratio) that enables normalization of the concerned AF lactatevalues when AF volume is variable as in oligo-hydromnios (IUGR), orpolyhydromnios (diabetes). The study involved term, and preterm IUGRpregnancies. Arterial umbilical cord blood and the AF were collectedsimultaneously during cesarean delivery. The study inferred that the L:Cratio in general decreased with increasing gestational age, and thatthere was no correlation to the arterial cord blood lactate and the AFlactate, but there was statistically significant correlation between thearterial cord blood lactate, and the AF-L/C ratio for the reason thatthe latter value enabled normalization of AF lactate values despite thevariable and unpredictable AF volumes.

What Causes Persistently Elevated Lactic Acid Levels and Severe Acidosisin the Neonate ?

The inquiry is important in the optimal neonatal care of the IUGR fetus,as the care of such baby is a continuum that may not terminate abruptlyat delivery. Soon after delivery, even the previously hypoxic fetusneonate starts to oxidize lactate to pyruvate aerobically, when NAD⁺ isreduced to NADH+H⁺ in many tissues of the body, and the pyruvate can beaerobically oxidized further in the citric acid cycle. If the neonate isdeficient in thiamine (a co-factor needed to oxidize pyruvate toacetyl-CoA that continues into the citric acid cycle, as discussedbefore), as thiamine stores are usually limited even in normal adult,the lactic acidosis will simply change into pyruvic acidosis, that is nobetter, but it can still abruptly change/reduce the urine lacticacid/lactate level though the acidosis itself is yet to be resolved.Accordingly, an invariable fall of blood lactate can be reflected in theadmixed urine.

It is imperative that as soon as delivered, the hypoxic baby, apart frombeing treated with oxygen, should be given thiamine and magnesium IV,proportional to the body weight, to ensure rapid resolution oflactic/pyruvic acidosis. Magnesium is a necessary co-factor inglycolysis/citric acid cycle, as essentially in all reactions in whichATP is a substrate, the true substrate is Mg²⁺-ATP, as the Mg²⁺diminishes the dense anionic character of ATP, for it to be functional(Martin D, 1983). If intrauterine lactic acidosis was diagnosed beforedelivery, immediate neonatal glucose supplements may not be needed, asthe pyruvate generated after the entry of supplemented glucose into thecells can compete with the conversion of existing lactate to pyruvate.When hypoxia is instantly resolved after the first breath, the bloodlactate is expected to be converted to pyruvate, as specified, whichthen enters the citric acid cycle, when the essential co-factors (likethiamine) are also present (unless the baby is neither breathing well,nor artificially oxygenated). Even in a normal adult, after a period ofanaerobic metabolism, when oxygen is available, the reversible chemicalreaction that forms lactate through lactate dehydrogenase (see FIG. 2)immediately reverses itself, the reversed reaction being aerobic, whenlactate is oxidized to pyruvate, with it's immediate entry into citricacid cycle. Entry of pyruvate into citric acid cycle (aided by thiaminethat generates one of the originators of the citric acid cycle, theacetyl-coA, from pyruvate), and lowering of it's concentration alsogreatly enhances the said reversal of the reaction involving lactatedehydrogenase (Guyton A C. 1981). With unlimited O₂ availabilityex-utero, the dominant reversal of the above reaction can be summated ina simplified manner as shown below.

Supplements of phosphorous is equally needed for the pivotal role itplays in oxidative phosphorylation, the ultimate step in the aerobicoxidation of pyruvate within the mitochondria. The phosphate group thatis added to ADP to form ATP is in fact derived from the inorganic

phosphate (H₂PO₄ ⁻) (the hydrogen phosphate) (see the section oxidativephosphorylation). It has to be noted that oxidation and phosphorylationare tightly coupled (Mayes P A) within the mitochondrial respiratorychain, and without concomitant phosphorylation, there is no catabolicoxidation of pyruvate, or it's subsequent intermediates of the citricacid cycle.

Optimal nicotinic acid levels are so essential to the neonate as theco-enzyme nicotinic acidadenine dinucleotide, the NAD⁺, ubiquitous inall cellular activities, is synthesized from this B-Complex factor. Amalnourished fetus-neonate deficient in needed vitamins and minerals cannot be adequately resuscitated without correction of such deficits.

Though a significant correlation was found between urine L/C ratio, andthe occurrence/severity of HIE (with IUGR/SGA babies as a subset ofinfants in this group) for diagnostic considerations in the foregoingstudies, monitoring the blood lactic acid/pyruvic acid/keto-acids isvaluable in these neonates for therapeutic considerations, as failure torapidly resolve blood lactic acidosis/pyruvic acidosis/ketoacidosisespecially in a SGA neonate that was chronically malnourished andhypoxic in-utero, can be reflective of vitamin/mineral deficiency. Amultivitamin mineral supplement is indicated to this subset of infants(as biotin, riboflavin and pantothenic acid are also involved for theoperation of citric acid cycle) to organize the whole metabolic chaosthat is invariable after their prolonged stay in a depriving and hostileuterine habitat. Once citric acid cycle is set to be operative and issustained, the multifaceted pathology of acidosis will resolve, withoutfurther clinical intervention in this regard

The pyruvate (originating from lactate) entering citric acid cyclerelieves acidosis by a ‘triple effect’, that is, byoxidation/elimination of excess lactate/pyruvate, resolution ofketoacidosis, as well as generation of bicarbonate, the citric acidcycle being the major generator of CO₂/bicarbonate, as the needed bloodbuffer base (in case the fetus is already not in hypercarbia/hypercapniathat can prevail with oligohydromnios). Hence, the persistent acidosisin the SGA neonate is due to continued lactic acidosis/pyruvicacidosis/keto-acidosis as well as lack of bicarbonate reserves, theetiology being common for all, that is the vitamin and mineraldeficiency, either singly or in any combination. Glucose has to beadministered with caution, while provision is given for resolution oflactic/pyruvic acidosis, when high lactate/creatinine ratio wasidentified in the AF, and excess blood lactic acid/pyruvic acid levelsare identified in the neonate. Obviously in these fetus-neonates withhigh lactate levels, hypoxia is far distressing than the hypoglycemia,with or without vitamin/mineral deficits. The real life-saving measuresthrough the perinatal period are—positive pressure O₂ therapy if theinfant's breathing is not optimal, and correction of vitamin/mineraldeficits. One may not wait for the blood vitamin/mineral reports toarrive, for supplementing them. They have to be given into the cordblood (while the blood is also drawn for lactic/pyruvic acid levels, andother needed blood chemistry) as soon as the cord is clamped, and whilethe baby is resuscitated, as finding a vein later can be time taking anddistressing, apart from being an unduly delayed maneuver. The umbilicalvein and the ductus venosus constrict immediately after birth, buttypically close in 1-3 hours after birth, and the

umbilical arteries obliterate in 3-4 days. Sodium bicarbonate is alsovery useful for immediate relief of acidosis. Glucose supplements shouldbe considered as soon as the pyruvate/lactate levels are found to befalling and approaching the normal range.

It is the aim of this invention to restore all IUGR/SGA afflictedfetuses/babies to their innate growth potential and optimum health,before and after they arrive into their terrestrial world.

This concludes the specification.

1. An embodiment of invention encompassing a method of treating thehuman fetal intrauterine growth restriction (IUGR) due to vascularinsufficiency of placental origin, involving maternal intravenous 25-50%hypertonic D-glucose (the dextroisomeric form of glucose) bolussupplements, 50-100 cc, two to three times in a day, and as it'sapplicable therapeutic modalities are exhausted with no evident relief,said treatment thereafter including administering isotonic D-glucose asdaily infusions through a catheter into the amniotic cavity, the saidcatheter insertion accomplished by a method of extraperitonealsuprapubic amniotomy encompassing a modified port catheter, namedSubcutaneously Implanted Pregnancy Port catheter (SIPP catheter).
 2. Aninvention encompassing a method of treatment for fetal intrauterinegrowth restriction of placental origin of claim 1, wherein the saidtherapeutically induced maternal hyperglycemia accelerates the placentalfacilitated diffusion of D-glucose (substrate) by the consequent insulineffects of recruiting exceeding number of the normally surplus cellmembrane carriers of D-glucose, responsive to the substrate (S) excess,such heightened number of carriers operating with a maximal velocity(Vmax), both the effects being in accordance with Michaelis-Menten modelof the substrate (S) effect on the Vmax, thereby relieving the fetalhypoglycemia, failing which the therapeutic transamniotic isotonicD-glucose supplements through a Subcutaneously Implanted Pregnancy Port(SIPP) catheter is the preferred additional modality of treatment,effectuating by-passing the placental impedance to D-glucose.
 3. Thesaid method of invention encompassing claim 1, wherein the fetaltransamniotic isotonic D-glucose supplements are necessarilycomplimented by prior and concommitant maternal hypertonic D-glucosesupplements, as the placental glucose requirements and functions are ashigh as or exceeding those of the fetal, the most important placentalfunction being an ongoing fetal supply of it's carbohydrate reserves aslactate, through placental lactate/H⁺ co-transport, at times when thematernal supplies lapse.
 4. An invention encompassing a method oftreatment for fetal intrauterine growth restriction of placental originof claim 2, wherein the maternal hyperglycemic state is therapeuticallyso induced that it differs maternal diabetes mellitus in it's effects,that in the preferred therapeutic measure— (1) fetal hyperglycemia isnot induced, whereas it's hypoglycemia is corrected, (2) the inducedmaternal hyperglycemia is transient, (3) maternal ketosis is notresulted and so are the fetal anomalies, said anomalies being consequentto maternal ketosis of the first trimester, prevailing in uncontrolledmaternal diabetes mellitus.
 5. An invention encompassing a method oftreatment for fetal intrauterine growth restriction of placental originof claim 1, wherein the induced fetal normoglycemia by maternalintravenous and transamniotic D-glucose supplements is operative insubstantive oxygen/ATP salvage, effectuated through major fetalmetabolic pathways, by: obviating oxygen consuming beta oxidation offree fatty acids and thereby averting ketoacidosis, the insulinresulting from normoglycemic status being antilipolytic; obviating fetalbody protein breakdown for energy requirements, which otherwise is aprocess of exceeding oxygen/ATP consumption, many amino acids enteringcitric acid cycle with ‘ATP debt’ as the relatively non-toxic ureaproduction from toxic ammonia of protein break-down demanding high ATPneeds.
 6. An invention encompassing a method of treatment for fetalintrauterine growth restriction of placental origin of claim 2, whereinthe induced fetal normoglycemia by maternal intravenous hypertonicD-glucose treatments with or with out concomitant transamnioticD-glucose supplements is deemed to— (1) improve fetal hypercapnia by:(a) the fetal normoglycemia induced lipogenesis sequestrating CO₂, as inthe synthesis of Palmitate from acetyl CoA and melonyl-CoA, 7 moleculesof carbon dioxide are engaged cyclically, relieving placental burden ofCO₂ disposal; (b) urea synthesis incorporating/eliminating CO₂,perpetuation of it's cyclic maneuver effectuated by predominantlyD-glucose derived ATP, (2) improve fetal hypoxia by: (a) obviating betaoxidation and the consequent O₂ needs by 33%; (b) obviating fetal bodyprotein breakdown for energy needs, the amino acid metabolic path waysdeemed worse than lipids in their O₂/ATP demands; (c) placental iron‘active transport’ increasing fetal mean corpuscular hemoglobinconcentration (MCHC) and improved oxygen carrying capacity, said ironactive-transport effectuated by predominantly D-glucose derived ATP; (d)higher MCHC further improving fetal polycythemia and the laminar flow offetal and placental vessels, normalizing ‘critical closing pressures’and oxygen transport; (e) heightening placental/fetal L-arginine activetransport needed of nitric oxide synthesis subject to improvingfeto-placental vasculogenesis, vasorelaxation and thereby overalloxygenation, effectuated by predominantly D-glucose derived ATP, (3)improve fetal oliguria/oligohydromnios by: (a) fetal D-glucose/citricacid cycle generated ATP operative in fetal urea cycle/urea production,responsible for urea-induced fetal osmotic diuresis; (b) highercirculating maternal glucose itself improving amniotic fluid volume byosmotic effects, (4) improve fetal acidosis by: (a) the CO₂ produced inpredominantly glucose-operative citric acid cycle generating body'sbicarbonate base reserve; (b) obviating beta oxidation of fats throughglucose induced optimal insulin levels antagonizing lipolysis, otherwisedeemed to generate excess of acetyl-CoA precluded to enter citric acidcycle, and fated for ketoacidosis; (c) the available D-glucose furtherproviding needed oxaloacetate and operative citric acid cycle, toincorporate normally derived acetyl-CoA, otherwise fated forketoacidosis; (d) D-glucose induced lipogenesis utilizing hydrogen ions,generated to a greater extent from the universally operative hexosemonophosphate shunt needed for the riboses of the fetal DNA/RNA, 28molecules of hydrogen ions participating in synthesizing a singlemolecule of palmitate via D-glucose induced fatty acid synthesis, (5)improve fetal hypertriglyceridemia by the induced fetal normoglycemicstatus producing adequate insulin antagonizing the lipolytic action ofthe enzyme lipoprotein lipase, such fetal lipolysis otherwise subject toesterification of liberated free fatty acids and glycerol intotriglycerides in the fetal tissues, (6) improve growth and maturation ofvital organs like fetal brain, by the optimal levels of D-glucoseparticipating in rapid ‘Lipogenesis via Glycolysis Abbreviated Citricacid Cycle’ (LGACC), wherein—2 citrate molecules instead of one, fromone molecule of D-glucose are diverted into fatty acid synthesis said2-citrate diversion needed of rapid fetal neuronal lipogenesiseffectuating four times less of absolute oxygen expenditure and twotimes less of absolute D-glucose expenditure, than one citratediversion; a substantive number of D-glucose molecules so subjected tolipogenesis are deemed to by-pass many steps of citric acid cycle, yetproducing optimal ATP due to exceeding amount of acetyl-CoA synthesisvia glycolysis being invariable, as the needed building blocks ofbrain's phospholipids/glycolipids; the therapeutic D-glucose supplementssufficiently aiding D-glucose needed in set unit time for the said2-citrate diversion for the brain's rapidly accomplished neuronallipogenesis, wherein the absolute D-glucose requirements are reduced bytwo times, while 4 times the otherwise absolute use of oxygen/ATP isobviated, a means of the therapeutic D-glucose reducing it's ownrequirements by 200% in absolute amount, while compensating for oxygenlack by 400% in absolute amount, during the process of rapid fetal brainneurogenesis, (7) improved fetal D-glucose/citric acid cycle generationof ATP, ubiquitous and essential: (a) for all feto-placental cellularactivities; (a) for active transport needed for transplacental passageagainst concentration gradient, of direly needed fetal growth factors,yet scarce in the maternal compartment, (8) improve over all fetalacquisition of nutrients/elements by placental transport, fetalsynthesis, or by added means as the IUGR diet, effectuating: (a) aminoacid transport—either by facilitated diffusion becoming operative,mostly controlled by glucose induced circulating insulin, when also thematernal-fetal amino acid ratio is more than 1, the IUGR diet providingessential amino acids needed of such gradient, or the D-glucose derivedATP mediated active transport becoming operative, when maternal-fetalamino acid ratio is less than 1, whereas the fetus itself is subject tosynthesizing in substantive number, the non-essential amino acids fromD-glucose derived carbohydrate precursors; (b) free fatty acidtransport—by simple diffusion down the concentration gradient, suchgradient created by maternal peak of free fatty acids, further helped bythe essential fatty acids from the IUGR diet, whereas the fetus itselfis subject to synthesizing in substantive amount, free fatty acids fromsupplemented D-glucose; (c) vitamins, minerals and trace elementstransport—by D-glucose derived ATP driven active transport, irrespectiveof maternal levels, such fetal acquisition further helped by IUGR-dietimprovising exceeding substrate (S) concentration, leading to Vmax ofthe carriers involved in placental transport, said carriers in turnmaximally recruited, subject to Michaelis-Menten model of enzyme/carriermediated reactions, (9) improvement of fetal hyperlacticemia or lacticacidemia—consequent to D-glucose therapy improving fetal hypoxia bysubstantive means, further helped by D-glucose generated ATP drivenactive transport of vitamin/mineral supplements, the supplementedthiamine aiding pyruvate entering citric acid cycle, thereby heighteningthe reversible lactate dehydrogenase reaction oxidizing lactate topyruvate, (10) improvement of placental/fetal nitric acid synthesis: byD-glucose generated ATP driven placental L-arginine uptake required ofnitric oxide synthesis that in turn needing as coenzyme, the NADPH+H⁺from D-glucose mediated pentose phosphate pathway of carbohydrateinterconversion, the said nitric oxide effectuating: (a) vasodilatationof the sinusoidal spaces of the placental circulation, normallyunresponsive to auto-regulation operative elsewhere in the body, therebyimproving the placental impedance; (b) vasodilatation of fetal vesselsincluding the umbilical vessels, subject to improving the vascularcompliance to over-ride their ‘critical closing pressure’; (c)preventing fetoplacental platelet aggregation and vaso-occlusion,improving over-all blood flow.
 7. An invention encompassing a device ofperipherally inserted Subcutaneously Implantable Pregnancy Port (SIPP)and catheter (port-catheter) of claim 1, configured to be an obstetricsurgical instrument for an extraperitoneal access of the amniotic cavityof a pregnant patient with an IUGR fetus, as a means of ongoing‘transamniotic fetal supplementation’ of isotonic D-glucose, wherein—(a) the said device comprising a generally in-part-sphericallystructured implantable port with a reservoir body made of light weightmedical grade plastic with an under surface concave shaped, thereservoir body also having a perimeter plate with apertures placedequidistant in it's three quadrants to be sutured to the subcutaneousplane of the port pocket, the remaining port quadrant coupling through alocking collar with a port stem or segment devised as a bifurcatingoff-shoot of the said port-catheter, (b) the said port of the SIPPdevice containing a dome or diaphragm shaped septum of 2 centimeterdiameter or more, made of medical grade silicone elastomer, is devisedto be punctured by needle, and capable of resealing upon removal, (c)the said port through the said locking collar, of similar material isconnected to a port stem or segment, off-shooting from the port catheterof polyurethane the said port-catheter configured to be having adiscrete proximal end and a discrete distal end, and comprised of aninternal diameter of 0.89 mm, and a length of 50-70 cm, though higherdimensions are not precluded, (d) the said discrete distal portion ofthe port-catheter, distal to the off-shoot of the port stem/segment isset forth as a trumpet segment of 2-3 cm length, terminating in a 1 cmdiameter detachable silicone rubber trumpet ensheathed over a plasticunderstructure, with the silicon flat sheet of the trumpet with noplastic underlay devised to be punctured with a 18-19 gauze needle topass in a guide-wire for relieving any occlusion block in theport-catheter, the guide-wire's passage made easier by the trumpetsegment devised as a direct continuation of the rest of the catheter,(e) the said discrete proximal end of the port-catheter is set forthwith a polyurethane ‘attachable-stabilizer’ devised as a winged cuffwith an axial slit, the cuff-slit opened to be glued to the exterior ofthe proximal SIPP catheter, immediately outside the myometrium of thelower uterine segment, while the wings' marginal apertures are suturedto the superficial myometrium, following the amniotomy catheterinsertion, (f) the distrete proximal catheter with a open terminal endto be positioned intraamniotic is devised thinner, and the discretedistal catheter coupling with the port is devised thicker with also awide luminal caliber, not to be blocked by solid particulate matter ofthe amniotic fluid, (g) accessory parts integral to the function ofcatheter insertion are—a puncture dilator (similar to a vein dilator) of0.89 mm internal diameter, a regular 18-19 gauze needle, 8-10 cm length,a steel guide wire of 0.64 mm diameter and a length ranging 55-75 cmthough higher dimensions are not precluded.
 8. The SIPP devise of claim7 configured for insertion into the amniotic cavity for infusingisotonic D-glucose supplements to a fetus inflicted with IUGR, it'soperation encompassing a particular sequence of a surgical methoddevised as Sumathi Paturu's technique of minimally invasiveextraperitoneal suprapubic uterine approach, with the surgical procedurecomprising— (1) for an early morning elective surgery, preparing thepatient the night before by distending her bladder to reach 4-5 cm abovethe pubic symphysis, by placement of a folley's catheter with it's bulboccluding the internal urethral meatus, such bladder distensioninstrumental in lifting the peritoneum off the lower abdominal wall, sofacilitating an extraperitonial suprapubic pelvic approach, (2) in anarea on the abdominal wall medial to the right anterior superior iliacspine, the proposed port-site, a 1 cm incision is made and a Hankcervical dilator of suitable length and preferred small diameter size isused to create a subcutaneous tunnel from the port site, with the saiddilator ensheathed in a suitable straight urinary catheter, (3) a 2.5 cm(1 inch) transverse incision is made above the symphysis pubis (thesymphysis-site) down to the rectus fascia, and the sheathed Hank dilatortraversing the subcutaneous tunnel is brought out through this incisionwhere from it is removed through the cut widened urinary catheter, andthe SIPP catheter is passed thereafter through the urinary catheter tobe brought to the symphysis destination, and in situations a straightmaneuvering is impractical, the tunneling instruments are brought outmidway at an inguinal incision, to repeat a similar procedure, (4)through the suprapubic incision the exposed rectus sheath is cutvertically as the distended bladder not covered by the parietalperitoneum of the lower anterior abdominal wall is visualized, whereinthrough the incision the blade of a small L-shaped retractor is insertedto traverse vertically above anterior to the bladder to reach theperitoneal shelf that overlies it, (5) the bladder is then allowed toempty slowly, as the retractor along with is moved down slower, withit's vertical position gradually changing to horizontal, so as when thebladder reaches pelvic position, the retractor assumes a horizontalposition that keeps off the peritoneal shelf above it to performextraperitoneal lower uterine amniotomy, and separating the peritoneumoff the superior surface of the bladder traversing the incision level init's descent into the pelvis further facilitating the view of the barelower uterine segment, (6) the proximal end of the SIPP catheter isintroduced through the bare lower uterine segment using a needle and aguide wire, and the guide wire thereafter let-out through the openedtrumpet terminal, (7) a 5-10 cm of intrauterine length of the SIPPcatheter is required, and an axially slit attachable winged cuff isglued with biocompatible adhesive to encircle the SIPP catheter at it'suterine entry, whereas the cuff wings are sutured to the superficialmyometrium of the lower uterine segment, (8) the retractor beneath theperitoneal shelf is removed, and the fascial incision closed, whileallowing the SIPP catheter to stay in the subcutaneous plane over whichthe skin incision is sutured, at least 10-15 cm of the SIPP catheterbeing redundant in the extraperitoneal pelvis, allowing bladderdistension and the uterine rise, (9) the incision at the port-site iswidened, and the port and distal structures of the SIPP catheterintroduced into the port-pocket, wherein the port is sutured to thetissues through three of the port apertures with non-absorbablematerial, and the port-site incision closed thereafter.
 9. A method ofclaim 8, wherein when the peritoneum is still attached to the loweruterine segment as the bladder itself balloons into the abdominalcavity, and two layers of peritoneum covering the lower uterine segmentare seen while the bladder peritoneum is separated allowing the bladderto recede to it's pelvic position, the extraperitoneal approach toaccess the bare lower uterine segment encompasses a sequence of stepsas— (1) a small 1 cm transverse incision is made over both theperitoneal layers situated anterior to the lower uterine segment, and astraight urinary catheter is passed between the uterine myometrium andthe posterior fold of the cut peritoneum, and the tip of the urinarycatheter maneuvered down to reach the uterovesical junction, (2) theurinary catheter tip is picked up anterior to the uterovesical fold ofperitoneum, and brought upon to the suprapubic area, wherein it's tip iscut for the proximal end of the SIPP catheter to be introduced into theurinary catheter to reach the destination of the bare lower uterinesegment, traversing retroperitoneally behind the posterior peritoneallayer, the retropubic procedure aided by a culdoscope, if necessary, (3)through the peritoneal incision the straight urinary catheter is removedover the SIPP catheter it ensheathed, when the amniotomy insertion ofthe SIPP catheter through the bare lower uterine segment is performedusing a needle and a guide-wire, following which both the layers ofperitoneum are sutured separately, while the SIPP catheter is situatedwholly extraperitoneal within the pelvis.
 10. A method of amniotomy ofclaim 8, wherein if the uterus can not be approached suprapubically, thefollowing procedural steps are indicated—(a) keeping the bladderdistended, the bare lower uterine segment is tangentially approached atan angle 45 degrees from the midline sagital plane, through a long 18-19gauge needle 8-10 cm in length, followed by a guide-wire, undermandatory ultrasound guidance, (b) the uterine entry differentiated frombladder entry, through the orange colored urine, by prior pyridiumintake of the patient, (c) following the track of guide-wire entry, theuterus is approached through a small grid-iron incision, with rest ofthe extraperitoneal amniotomy performed in a similar manner as in thesuprapubic approach, whereas the proximal SIPP catheter is brought tothe surgical site traversing the subcutaneous plane, (d) when the loweruterine segment is found covered by two layers of peritoneum, the SIPPcatheter can reach the bare lower uterine segment ensheathed in astraight urinary catheter as in supra-pubic approach, the lifted pelvicperitoneum by bladder distention, and the roomier lateral pelvic floorallowing better uterine access than the retropubic space.
 11. The methodof claim 8 of the transamniotic fetal nutrition of the said IUGR fetusis aseptically accomplished through a ‘sterile patch’ technique, whereina sterile patch or any sterile skin barrier is taped to the cleaned portsite of the maternal abdomen, and a needle puncture accomplished throughthe untouched center of said sterile skin barrier, while the needlecontact with the naked skin of the port site is precluded.
 12. A methodof invention wherein the IUGR fetus/neonate subject to chronic or acuteperinatal hypoxia/asphyxia showing persistent lactic acidemia andacidosis is treated with IV vitamin/mineral supplements preferably intothe cord soon after birth, apart from oxygen support to counter acidosisas a ‘triple effect’ by (1) relieving lactic acidosis/pyruvic acidosis,(2) relieving ketoacidosis, and (3) generating base reserve through CO₂of the citric acid cycle—the triple effect operative mostly throughthiamine facilitated pyruvate entry into citric acid cycle therebyheightening lactate oxidizing to pyruvate, the step further aided bywithholding neonatal D-glucose supplements when the perinatallactate/pyruvate levels were found elevated, needing it's rapid andpreferential catabolic disposal.
 13. The claim of 1, wherein the fetalIUGR treated with IV hypertonic D-glucose with or without transamnioticisotonic D-glucose are evaluated/monitored/treated at base line andsubsequently— (1) with amniotic fluid (AF) lactate (AF-LA) levels—whenfound higher at base line with lowered AF pH and lowered BPPS,indicating fetal hypoxia, yet with intrinsic fetal lactate/carbohydratereserves amenable for an aerobic recovery—maternal continuous oxygentherapy (COT) preceding D-glucose therapy is thereby indicated, (2) withfetal BioPhysical Profile (BPP) score (BPPS) of 0-10—having quantitativepower to proportionate the IV DG₂₅₋₅₀ treatment, wherein fetal hypoxiaand fetal intolerance of D-glucose subject to lowering BPP score (lessthan 8) and lowering fetal blood pH, the latter contextually linked tofetal lactic acidosis, such quantitative monitoring power of BPP scoretherefor chosen as proxy to infrequently done AF-LA levels/AF pH, (3)with normal AF-LA and normal AF pH, yet having lowered BPPS—maternal IVtherapy with hypertonic D-glucose alone is indicated, (4) with fetalheart rate (FHR) tracings during each IV DG₂₅₋₅₀ treatment—as adverseFHR changes are reflective fetal intolerance of D-glucose treatmentconsequent to fetal hypoxia and anaerobic glycolysis, an intermittentoxygen therapy (IOT) reverting back the changes is thereby indicated,(5) with the mother on IOT about the time of daily IV DG₂₅₋₅₀ therapy—iffails in weaning challenge off oxygen therapy, with accompanying adverseFHR changes or falling BPP scores—effective dose D-glucose with IOTcontinues to be indicated, (6) with the mother on IOT—if showing DG₂₅₋₅₀intolerance with adverse FHR changes, or fallen BPP scores, who thenimproved with COT, an effective dose D-glucose with COT is thereafterindicated, (7) with the mother on COT—if showing IV DG₂₅₋₅₀unresponsiveness by adverse FHR changes and low BPP scores, yet withnormal or low AF-LA levels, a transamniotic D₅-glucose fetal supplementis the therapeutic modality additionally indicated.
 14. The invention ofclaim 1, wherein the fetal IUGR treated with maternal IV hypertonicD-glucose therapy being intended for extended duration, a percutaneouslyinserted central venous catheter, exemplified by Broviac's catheterdelivering the said therapy is inserted into the maternal brachial veinat the cubital fossa, by means of a needle and guide wire, or by anysuitable means, with Sumathi Paturu's subcutaneous tunneling technique,the sequential steps of which are as follows— (a) by mapping the surfaceanatomy of the brachial vessels about the cubital fossa, a small 1 cmcut is made over the proposed venipuncture (venotomy) site lifting askin fold, and cutting with scissors, (b) the smallest size Hegarcervical dilator, configured as a smoothly curved sigmoid shapedinstrument, ensheathed in a straight urinary catheter of a sizesufficient to allow free movement of the dilator is chosen as thetunneling instrument, and from the venotomy site, a subcutaneous tunnelis made to the chosen skin exit site on the medial aspect of theforearm, wherein through a 1 cm skin incision, the tunneling instrumentis brought out, (c) the Hegar dilator is removed from it's urinarycatheter sheath, by allowing to retreat it's course through the venotomysite, (d) the urinary catheter tip is cut and widened for the proximalend of the Broviac catheter to be introduced and brought to the venotomysite, as the urinary catheter is removed thereafter from the venotomysite over the Broviac catheter it had ensheathed, while the Broviaccatheter tip brought to the venotomy site is inserted into the brachialvein through a needle and guide-wire, or through the conventional venousaccess.